Transcript
2014 SWEDRES|SVARM Consumption of antibiotics and occurrence of antibiotic resistance in Sweden
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A report on Swedish Antibiotic Utilisation and Resistance in Human Medicine (Swedres) and Swedish Veterinary Antibiotic Resistance Monitoring (Svarm) Published by: Public Health Agency of Sweden and National Veterinary Institute Editors: Jenny Hellman and Olov Aspevall, Public Health Agency of Sweden Björn Bengtsson and Märit Pringle, National Veterinary Institute Addresses: Public Health Agency of Sweden SE-171 82 Solna, Sweden Phone: +46 (0) 10 205 20 00 Fax: +46 (0) 8 32 83 30 E-mail:
[email protected] www.folkhalsomyndigheten.se National Veterinary Institute SE-751 89 Uppsala, Sweden Phone: +46 (0) 18 67 40 00 Fax: +46 (0) 18 30 91 62 E-mail:
[email protected] www.sva.se ISSN 1650-6332 ISBN 978-91-7603-360-9 (pdf) ISBN 978-91-7603-361-6 (print) Article no. at Folkhälsomyndigheten 14027 This title and previous Swedres and Svarm reports are available for downloading at www.folkhalsomyndigheten.se/publicerat-material/ or www.sva.se. The title can also be ordered from the webshop at: www.folkhalsomyndigheten.se/publicerat-material/ or Department of Animal Health and Antimicrobial Strategies, National Veterinary Institute, SE-751 89 Uppsala, Sweden Phone: +46 (0) 18 67 40 00 Fax: +46 (0) 18 30 91 62 E-mail:
[email protected] Text and tables may be cited and reprinted only with reference to this report. Images, photographs and illustrations are protected by copyright. Suggested citation: Swedres-Svarm 2014. Consumption of antibiotics and occurrence of antibiotic resistance in Sweden. Solna/Uppsala ISSN 1650-6332 Print & Layout: Edita Västra Aros AB Cover by Ingvar Westerdahl/Thomas Isaksson
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Preface The 2014 Swedish report from the monitoring of antibiotic resistance and antibiotic consumption in human and veterinary medicine, Swedres-Svarm, is an integrated report from the Public Health Agency of Sweden and the National Veterinary Institute that includes data from humans, animals and food. The report is a result of the successful collaboration between the relevant sectors in Sweden. Through a ‘One Health’ approach, we stand a better chance to respond to the challenges of antibiotic resistance and the way we use, and sadly, misuse, antibiotics. Veterinary and human medicine must act and work in a synchronised manner, and this is the reason why a large number of Swedish governmental authorities have been working together to prepare a joint action plan against antibiotic resistance in 2014. In parallel with that work, a joint communication strategy has been adopted that will ensure greater impacts for whatever actions are taken. During the last year, several initiatives have been taken that cross traditional political and national boundaries and involve many of our experts. Of particular importance in a Swedish context was a high-level meeting focusing on a global programme for surveillance of antibiotic resistance that was co-hosted by the WHO, the
Public Health Agency of Sweden and the Swedish Ministry of Health and Social Affairs. This year’s report shows that Sweden is still in a very favourable situation and that the levels of resistance continue to be low. In some areas of the veterinary sector, we have even seen some improvements relative to previous years. Thankfully, the screening of all breeding herds once again showed that MRSA has not spread among breeding pigs in Sweden. We can conclude that in a global perspective Sweden is better off compared to most countries, but we are far from being spared the problems associated with antibiotic resistance. Consequently, further efforts are needed to counter the selection and spread of resistance, and one key component in that work is high-quality information about the current situation in the country. This December it will be 70 years since Sir Alexander Fleming held his now famous Nobel Laureate lecture in Stockholm. Even then he warned the audience about the perils of misusing antibiotics and what would happen if we chose not to use them wisely. His warnings still hold true, and hopefully there is still time to act upon them in truly global manner.
Johan Carlson
Jens Mattsson
Director General
Director General
Public Health Agency of Sweden
National Veterinary Institute
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Contributors and participants Authors Swedres
Other contributors in Svarm
Public Health Agency of Sweden Olov Aspevall, Bo Aronsson, Petra Edquist, Malin Grape, Sara Hæggman, Mats Hedlin, Jenny Hellman, Jerker Jonsson, Sonja Löfmark, Eva Morfeldt, Barbro Mäkitalo, Christer Norman, Magdalena Prioux, Karin Sjöström, Gunilla Skoog, Anders Ternhag, Tomas Söderblom and Thomas Åkerlund
National Veterinary Institute Kerstin Ekström, Maria Finn, Mattias Myrenås and Eva Säker
Medical Products Agency Hans Olaisson Department of Infectious Diseases, Danderyds Hospital, Stockholm Jesper Ericsson Department of Clinical Microbiology, Karolinska University Hospital, Solna Christian Giske National Reference laboratory for Antibiotic Resistance, Växjö Hospital Gunnar Kahlmeter National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital Hans Fredlund, Susanne Jacobsson and Magnus Unemo Department of Communicable Disease Control, The County Council, Region of Halland Mats Erntell
Farm & Animal Health Maria Lindberg Swedish Board of Agriculture Kinfe Girma
Acknowledgements The analyse of the antibiotic consumption was made in close collaboration with the external group of antibiotic sales data of the Public Health Agency of Sweden: Ingrid Brännström, Jonatan Dahlqvist, Mats Erntell, Annika Hahlin, Mikael Hoffmann and Anastasia Nyman. Data on antibiotic use in relation to number of admissions and number of patient days in somatic hospital care during 2010-2014 were kindly provided by pharmacists in local Strama-groups. Strama collaboration group of the Public Health Agency of Sweden formerly the Strama advisory board. The national surveillance of antibiotic resistance would not have been possible without the contribution of data and active support of all the Swedish clinical microbiology laboratories.
Strama group, Kalmar County Per-Åke Jarnheimer Olsson
Complementary epidemiological information on clinical notifications has been performed by the local County Departments for Communicable Disease Control.
Authors Svarm
Data on antimicrobials for animals sold with special license were kindly provided by pharmaceutical companies.
National Veterinary Institute Björn Bengtsson, Karin Bergström, Stefan Börjesson, Anna Duse, Helle Ericsson Unnerstad, Christina Greko, Annica Landén, Oskar Nilsson, Märit Pringle and Julia Österberg.
Other contributors in Swedres National Board of Health and Welfare Andrej Leimanis
Kerstin Ortman and Hanna Arosenius at Eurofins Food & Agro, Skara for kindly provided SVA with clinical isolates and susceptibility results from clinical submissions from animals.
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Content Preface....................................................................................3
Zoonotic pathogens...........................................................63
Contributors and participants................................................4
Salmonella........................................................................63
Sammanfattning/Summary....................................................7
Campylobacter..................................................................67
Guidance for readers............................................................13
Clinical isolates from humans............................................68
Consumption of antimicrobials.........................................17
Isolates from blood cultures reported to ECDC/EARS-Net.........................................................68
Total consumption of antibiotics in humans.....................17 Antibiotics in outpatient care.............................................18 Gender differences.........................................................19 Antibiotics commonly used to treat respiratory tract infections, urinary tract infections and skin and soft tissue infections................................................19 Antibiotic consumption in children...............................23
Resistance in other bacterial species from blood cultures...........................................................................70 The annual resistance surveillance and quality control programme (ResNet).........................................71 Clostridium difficile...........................................................73 Neisseria gonorrhoeae........................................................75 Neisseria meningitidis.......................................................75
County data....................................................................25
Mycobacterium tuberculosis................................................76
Antibiotics in dentistry...................................................27
Clinical isolates from animals............................................77
In focus National campaign for improved patient safety...................................................................28
Pigs.................................................................................77
Antibiotics in hospital care................................................31
Sheep..............................................................................82
In focus A national IT tool for surveillance of healthcare-associated infections and antibiotic use.......34
In focus Risk factors for antibiotic resistant Escherichia coli in faeces of preweaned dairy calves........83
Adverse reactions related to antibiotic use........................36
Farmed fish.....................................................................84
Consumption of systemic antifungals................................37 Hospital care...................................................................37
In focus Svarmpat – monitoring of resistance in pathogens from farm animals.........................................85
In outpatient care...........................................................38
Horses.............................................................................86
Consumption of antibiotics in animals..............................38
Dogs................................................................................87
Comparison of antibiotic consumption in human and veterinary medicine.....................................................42
Indicator bacteria from animals.........................................92
Cattle..............................................................................79
Cats.................................................................................90 Escherichia coli..................................................................92
Antibiotic resistance..........................................................45
Enterococcus......................................................................94
Notifiable diseases..............................................................45
In focus SafeOrganic - studies on antibiotic resistance in organic and conventional pig production in EU.......97
Overview of sampling and culture results in humans.......45 ESBL-producing Enterobacteriaceae............................46 In focus ESBL producing Escherichia coli – food as a potential dissemination route to humans....................48
Background data, material, metods and references.........99
Methicillin-resistant Staphylococcus aureus (MRSA).......52
Materials and methods, consumption of antibiotics.......103
In focus MRSA in pigs in Sweden..................................58
Materials and methods, resistance in bacteria from humans.............................................................................107
Methicillin-resistant Staphylococcus pseudintermedius (MRSP)...........................................................................60 Vancomycin resistant Enterococcus faecalis and Enterococcus faecium (VRE)..............................................60 Streptococcus pneumoniae with reduced susceptibility to penicillin (PNSP).......................................................62
Demographics and denominator data...............................99
Materials and methods, resistance in bacteria from animals..............................................................................109 Svarm 2000-2014.............................................................113 References........................................................................115
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Sammanfattning/Summary Sammanfattning När det gäller antibiotikaresistens hos bakterier från människor och djur har Sverige en gynnsam situation sett i ett internationellt perspektiv. Detta bekräftar att vi har effektiva strategier för att främja rationell antibiotikaanvändning och begränsa spridning av resistenta bakterier bland djur och människor. Ändå beskriver årets rapport även ogynnsamma trender, t.ex. sjukhusutbrott med VRE (vankomycinresistenta enterokocker) och humana fall av Enterobacteriaceae med ESBLCARBA (betalaktamas med utvidgad spektrum som även har aktivitet mot karbapenemer) som smittats inrikes och där smittkällorna är okända. Detta betonar än en gång att arbetet med att optimera antibiotikaanvändningen, förebygga infektioner och minska spridningen av resistenta bakterier måste fortgå och ständigt förbättras.
Förbrukning av antimikrobiella medel Antibiotikaförbrukning inom humanmedicin Den totala antibiotikaförsäljningen (öppenvård och slutenvård) minskade med 4 procent (från 13,4 till 12,8 DDD per 1 000 invånare och dag). I öppenvården (inkluderar all antibiotika försålt på recept) minskade försäljningen med 4 procent, från 343 till 328 recept per 1 000 invånare och år. Minskningen sågs i alla åldersgrupper och den största förändringen gäller barn 5–14 år (8 procent). Antibiotikaförsäljningen minskade i samtliga 21 län. Skillnaden mellan länen är dock fortfarande stor, och varierar från 359 recept per 1 000 invånare och år i Stockholm till 260 i Västerbotten. Minskningen omfattade de flesta antibiotikagrupper med undantag för pivmecillinam, nitrofurantoin, trimetoprim med sulfonamider, penicillin med klavulansyra samt makrolider. Pivmecillinam och nitrofurantoin är förstahandsmedel för nedre okomplicerad urinvägsinfektion och den ökade användningen bedöms bero på ökad följsamhet till nationella behandlingsrekommendationer. Den ökade försäljningen av makrolider kopplas till det leveransproblem av erytromycin som uppstod under våren 2013. Betalaktamaskänsliga penicilliner tillsammans med tetracykliner var de antibiotika som förskrevs mest på recept under 2014. Antibiotika som ofta används mot luftvägsinfektioner (LVI) är den antibiotikagrupp som används mest, och det är även i denna grupp som försäljningen minskade mest under 2014 (7 procent). Denna minskning är främst relaterad till en nedgång i användningen av betalaktamaskänsliga penicilliner (8 procent) och tetracykliner (10 procent). Behandlingen av nedre urinvägsinfektioner (UVI) hos kvinnor ser ut att följa nationella behandlingsrekommendationer. Under 2014 minskade den totala försäljningen av UVI-antibiotika till kvinnor 18–79 år något (1 procent) jämfört
med 2013. Under året fortsatte den positiva trend som setts under de senaste åren med en ökad försäljning av förstahandspreparaten pivmecillinam och nitrofurantoin, i stället för de breda och mer resistensdrivande preparaten trimetoprim och fluorokinoloner. Försäljningen av trimetoprim minskade med 13 procent under 2014 och fluorokinoloner med 2 procent. Den totala försäljningen av antibiotika mot nedre UVI hos män i åldersgruppen 65 år och äldre minskade något (1 procent) under 2014 jämfört med 2013. Fluorokinoloner är fortfarande det preparat som används mest bland UVI-antibiotika till män i denna åldersgrupp, och under 2014 fortsatte denna försäljning att minska med 2 procent. Däremot ökade försäljningen av pivmecillinam och nitrofurantoin även till män, med 20 respektive 12 procent mätt som recept per 1 000 invånare och år. Försäljningen av antibiotika förskrivet av tandläkare minskade med 9 procent under 2014 jämfört med 2013, från 26,0 till 23,6 recept per 1 000 invånare och år (J01 inklusive metronidazol P01AB01). Störst minskning sågs för amoxicillin (13 procent) och klindamycin (14 procent). Under 2014 ökade den totala antibiotikaförbrukningen på sjukhus något jämfört med 2013 (mätt som DDD per 100 vårddagar och DDD per 100 vårdtillfällen). Användningen av betalaktamaskänsliga penicilliner, cefalosporiner och amino glykosider låg kvar på samma nivå medan försäljningen av betalaktamas-resistenta penicilliner, fluorokinoloner, karbapenemer och penicilliner med betalaktamashämmare fortsatte att öka likt föregående år. Användningen av penicilliner med betalaktamashämmare har ökat kraftigt på svenska sjukhus under de senaste åren, och 2014 var ökningen 7,3 procent. Användningen av karbapenemer har ökat marginellt. Karbapenemer och piperacillin med tazobaktam används oftare, och det finns en möjlig koppling till ett ökande antal infektioner orsakade av bakterier med ESBL (ExtendedSpectrum Betalaktamases). I länen varierar andelen bredspektrumantibiotika (fluorokinoloner, cefalosporiner, karbapenemer och piperacillin med tazobaktam) av den totala antibiotikaförbrukningen på svenska sjukhus, från 28,6 procent i Värmland till 37,6 procent i Östergötland. Sett över en längre tid har försäljningen av antibiotika på slutenvårdsrekvisition (alla sjukhus inklusive viss förbrukning inom äldreboenden och andra vårdenheter) gått från en hög användning av breda preparat till smala antibiotikapreparat. Sedan 2008 är betalaktamasresistenta penicilliner (J01CF) och betalaktamaskänsliga penicilliner (J01CE) de antibiotikagrupper som försäljs mest på slutenvårdsrekvisition.
Försäljning av antimykotika Under 2014 var den totala användningen av antimykotika på svenska sjukhus densamma som 2013, det vill säga 61 DDD per miljon invånare och dag. Liksom tidigare är flukonazol det mest använda preparatet och utgör två tredjedelar av all sjukhusanvändning (39,5 DDD per miljon invånare och
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dag). När det gäller preparat med bredare antifungal täckning ökade amfotericin B med 28 procent och står nu för 16 procent av den totala förbrukningen. Under de senaste sex åren har försäljningen av echinokandinerna ökat och denna grupp utgör 12 procent av den totala förbrukningen. Tidigare var caspofungin det absolut dominerande preparatet i gruppen, men det har förlorat en stor del av sin dominans och utgör nu cirka 44 procent av den totala användningen. Anidulafungin och det nyare preparatet mikafungin står nu för 38 respektive 18 procent. Den totala förbrukningen av bredspektrumazoler är relativt oförändrad, men vorikonazol fortsätter att minska till förmån för posakonazol. Många landsting med universitetssjukhus har ökat förbrukningen av både andiulafungin och mikafungin och minskat sin användning av caspofungin.
Antibiotikaförbrukning inom veterinärmedicin Efter omregleringen av apoteksmarknaden 2009 finns indikationer på ett bortfall i statistiken när det gäller försäljning av antibiotika för djur. Bortfallet berör troligen främst läkemedel för injektion, men eftersom dessa utgör minst 70 procent av den totala förbrukningen är det svårt att bedöma trender sedan 2010. Den totala förbrukningen av antibiotika har dock minskat sedan mitten av 1990-talet, och det är troligt att det finns en sann minskning även sedan 2010. Databortfallen har troligen ingen större betydelse för statistik över läkemedel för medicinering av enskilda djur via munnen och för medicinering av grupper av djur via foder och vatten. Mellan 2010 och 2014 ses en påtaglig minskning av dessa två typer av antibiotikaprodukter (32 respektive 55 procent).
Jämförelse av förbrukning inom human- och veterinärmedicin Under 2014 förbrukades 60,5 och 10,2 ton antibiotika inom human- respektive veterinärmedicin. Mätt som milligram aktiv substans per skattad kilogram biomassa var förbrukningen 96,4 respektive 12,7 milligram per kilogram. Förbrukning inom humanmedicin dominerade alla antibiotikaklasser utom trimetoprim-sulfa och aminoglykosider.
Anmälningspliktig resistens ESBL-producerande Enterobacteriaceae År 2014 rapporterades totalt 8 902 fall av Enterobacteriaceae med betalaktamaser med utvidgat spektrum (ESBL) hos människa, vilket var en ökning med 9 procent jämfört med året innan. Ökningen skedde i 15 län, och liksom tidigare år var Escherichia coli den helt dominerande arten och förekom i 89 procent av fallen. Klebsiella pneumoniae var näst vanligast med 7 procent. Bakteriefynden gjordes framför allt i urinprov. Invasiva infektioner med ESBL-producerande bakterier ökade under 2014 till 520 anmälningar, från 402 året innan. En viss typ av ESBL, ESBLCARBA, har en bredare resistensmekanism, och bakterier med denna resistens blev under 2012 anmälningspliktiga både av den behandlande läkaren
och av laboratoriet som gjorde fyndet. Totalt 46 nya fall upptäcktes 2014, och de två vanligaste enzymtyperna var OXA-48 och NDM. Under året inträffade två inhemska smittspridningar med fyra personer inblandade, varav den ena spridningen skedde på sjukhus och den andra inom vård och omsorg utanför sjukhus. Dessa extremt resistenta bakterier är hittills ovanliga i Sverige men en ökad vaksamhet är nödvändig för att vi tidigt ska upptäcka dem och också kunna förhindra spridningen av dem inom vården, eftersom behandlingsalternativen vid en eventuell infektion är få eller inga. Hos djur förekommer Enterobacteriaceae med ESBLproduktion både som tarmkolonisation och som kliniska isolat, då främst från sår eller urogenitalia. Förekomsten är relativt låg, undantaget slaktkyckling där en stor andel av djuren bär på ESBL-producerande E. coli. Det har dock skett en signifikant minskning av förekomsten hos slaktkyckling och andelen positiva prov är nu jämförbar med situationen 2010 då problemet först uppmärksammades.
MRSA Totalt anmäldes 2 921 nya fall hos människa av meticillinresistenta Staphylococcus aureus (MRSA) 2014, vilket är en ökning med 19 procent. Andelen smitta utomlands och i Sverige var lika stora. Samhällsförvärvad smitta var vanligare bland de inhemskt smittade fallen (76 procent) än bland de utomlands smittade (50 procent), medan sjukhusförvärvad smitta var vanligare bland importerade fall (28 procent) än bland inhemska (8 procent). Invasiva infektioner med MRSA rapporterades hos 39 personer under 2014. Epidemiologisk spa-typning visade att de fem vanligaste spa-typerna var t223, t008, t044, t002 och t127. Andelen PVL-positiva MRSA hade minskat något till 35 procent jämfört med året innan. Förekomsten av MRSA hos djur är fortfarande låg i Sverige, vilket begränsar risken för spridning till människa. Under 2014 provtogs samtliga livdjursproducerande grisbesättningar och MRSA hittades inte. Däremot isolerades MRSA sporadiskt från häst, hund, katt, nötkreatur och igelkott. Hos hundar och katter dominerar samma typer av MRSA som hos människor, vilket tyder på att människor är smittkällan. Hos hästar är lantbruksdjurstypen MRSA CC398 vanligast.
MRSP Under 2014 anmäldes 39 fall av meticillinresistent Staphyl ococcus pseudintermedius hos hund (36 fall), katt (2 fall) och häst (1 fall). De anmälda fallen har minskat sedan 2009 då 130 fall anmäldes. Under 2014 rapporterades inget fall av MRSP hos människor till nationella myndigheter men MRSP är inte generellt anmälningspliktig i humansjukvården.
PNSP Under 2012 förändrades definitionen för anmälningsplikt av Streptococcus pneumoniae med nedsatt känslighet för penicillin (PNSP) till att gälla enbart isolat med MIC av penicillin större än 1 mg per liter, vilket har medfört en kraftig minskning av antalet anmälda fall. Totalt anmäldes 70 fall av PNSP
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under 2014. För att kunna följa effekten av vaccination mot pneumokocker samlar Folkhälsomyndigheten regelbundet in PNSP-isolat med MIC ≥ 0,5 mg per liter för serotypning. De vanligast förekommande serotyperna 2014 var 19F, NT, 35B, 19A, 23F, 14, 11A, 6B och 9V.
VRE År 2014 anmäldes 402 nya fall av vankomycinresistenta enterokocker (VRE) hos människa, vilket var en ökning med 77 procent jämfört med 2013. Merparten av isolaten var Enterococcus faecium, och liksom 2013 är nu vanB (281 fall) vanligare än vanA (110 fall). Tretton sjukvårdsrelaterade utbrott rapporterades under året i sex län, varav alla med E. faecium. Sju var med vanA och sex med vanB. Det största utbrottet inträffade i Gävleborgs län. Det började i september 2013 och avslutades under vintern 2014, och omfattade 314 fall.
Resistens hos zoonotiska smittämnen Salmonella är ovanligt hos djur i Sverige och isolerade stammar är oftast känsliga för antibiotika. Någon överförbar resistens mot tredje generationens cefalosporiner har aldrig påvisats och resistens mot antibiotikagruppen fluorokinoloner är mycket ovanligt. Svenska djur är en osannolik källa till Salmonella som orsakar invasiva infektioner hos människor eftersom sådana stammar vanligen tillhör andra typer än de som finns hos djur och dessutom ofta är resistenta mot kinoloner. Campylobacter-stammar från djur i Sverige är oftast känsliga för relevanta antibiotika och exempelvis är resistens mot erytromycin mycket ovanligt. Campylobacter som isoleras från människor är däremot ofta resistenta och det är därför osannolikt att de stammarna kommer från svenska djur. Vanligtvis behandlas inte infektioner orsakade av Salmonella eller Campylobacter med antibiotika, varken hos människor eller hos djur. Det innebär att det när det gäller infektioner hos människor framför allt finns data angående antibiotikaresistens för ett litet antal invasiva infektioner.
Resistens hos kliniska isolat från människor I det europeiska nätverket för resistensövervakning, EARSNet, ingår åtta olika bakteriearter. Endast isolat från blododlingar omfattas. År 2014 var det 16 svenska laboratorier som medverkade i EARS-Net. Totalt 15 laboratorier rapporterade till publiceringen av Swedres, det täcker cirka 80 procent av befolkningen. Sju laboratorier har även rappor terat övriga blodisolat under året och följande fynd gjordes 2014: Escherichia coli förekom i 26,4 procent av de positiva blododlingarna och S. aureus i 13,4 procent. De övriga sex bakteriearterna som ingår i övervakningen är viktiga men utgjorde en avsevärt mindre andel av fynden. Hos E. coli och K. pneumoniae har andelen cefalosporinresistenta (till största delen orsakad av ESBL-produktion) isolat ökat
varje år och uppgick till 5,4 respektive 4,0 procent 2014. Andelen MRSA av drygt 3 500 rapporterade S. aureus var 0,9 procent, vilket ur ett europeiskt perspektiv är lågt. VRE utgjorde 0,7 procent av E. faecium (3 fall), och för E. faecalis är läget oförändrat med inga rapporterade fall. Andelen PNSP av de knappt 800 S. pneumoniae var 6,3 procent. Den andra delen av den nationella resistensövervakningen är tillgänglig i applikationen ResNet, och i den undersöks samma bakteriearter som i EARS-Net. Alla kliniska laboratorier ombeds testa isolat från urinvägs-, sår- eller luftvägsinfektioner, med syftet att bättre kunna spegla situationen i öppenvården. Andelen resistenta bakterieisolat i de båda övervakningssystemen ligger på likartade nivåer. För vissa bakteriearter finns speciella övervakningsprogram och/eller speciallaboratorier som kan utföra analyserna. Det gäller dels tarmbakterien Clostridium difficile som kan orsaka svåra diarrétillstånd, dels bakteriearterna Neisseria gonorrhoeae (gonokocker), N. meningitidis (meningokocker) och Mycobacterium tuberculosis (tuberkulosbakterien). Andelen C. difficile-isolat som är resistenta mot erytromycin och klindamycin ökade något under 2014, medan den var densamma som 2013 för moxifloxacin. Ribotyp 027 ökade under 2014 till följd av utbrottet i Kronoberg (separat rapport). År 2014 var resistensen hos gonokocker mot cefixim 2 procent, vilket innebar en fortsatt minskning, och resistensen mot ceftriaxon var 0,3 procent. Detta är ytterst lovande eftersom ceftriaxon är ett viktigt medel för empirisk behandling av gonorré. Resistens hos M. tuberculosis är en ständigt aktuell frågeställning. Tuberkulos övervakas noggrant och situationen i Sverige är god.
Resistens hos kliniska isolat från djur Bakterier som orsakar sjukdom hos djur är fortfarande oftast känsliga för de antibiotika som vanligen används. Till exempel är bakterier som orsakar luftvägsinfektioner hos lantbrukets djur och hästar generellt känsliga för bensylpenicillin. Penicillinresistens är däremot vanligt hos S. pseudintermedius från hundar och förekommer hos S. aureus från hästar och Staphylococcus felis från katter. Resistens hos E. coli från olika djurslag förekommer också men är vanligast i isolat från träckprover från unga kalvar. Resistensundersökning är motiverat för att välja lämpligt antibiotikum vid behandling, särskilt för stafylokocker och E. coli.
Indikatorbakterier från friska djur Resistens hos E. coli, E. faecalis och E. faecium från tarmfloran hos friska djur kan användas som indikator för utbredningen av antibiotikaresistens hos bakteriefloran i en djurpopulation. Indirekt kan den även visa på omfattningen av antibiotika användning till djuren. I Sverige är förekomsten av resistens hos dessa indikatorbakterier låg hos de flesta undersökta djur slag och situationen är gynnsam i ett internationellt perspektiv.
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Summary The situation in Sweden regarding antibiotic resistance in bacteria from humans and animals is favourable when seen in an international perspective. This confirms that the Swedish strategies to promote rational use and to contain antibiotic resistance in bacteria from animals and humans have been effective. Still, this year’s report also reports some unfavourable trends, for example, a large hospital in Sweden has been hit with VRE (vancomycin resistant enterococci) and there have been domestic human cases of Enterobacteriaceae with ESBLCARBA (extended spectrum beta-lactamase with activity against carbapenems) where the sources of infection are unknown. This highlights once again that efforts to optimize antibiotic use, prevent infections, and minimize dissemination of antibiotic resistance must be ongoing and continually improved activities.
Consumption of antimicrobials Antibiotic consumption in humans The total consumption (including outpatient care and hospital care) of antibiotics decreased by 4 percent in 2014 compared to 2013 (from 13.4 DDD to 12.8 DDD per 1 000 inhabitants and day). In outpatient care (including sales on prescriptions), antibiotic sales decreased by 4 percent from 343 prescriptions per 1 000 inhabitants and year in 2013 to 328 in 2014. This decrease was seen in all age groups and was most evident in the age group 5–14 years (an 8 percent reduction). In total, a decreased number of antibiotic prescriptions was seen in all 21 Swedish counties in 2014. There are still significant regional differences between parts of Sweden, and the number of prescriptions per 1 000 inhabitants ranges from 359 in Stockholm County to 260 in Västerbotten County. The decrease encompasses most antibiotic groups with the exception of nitrofurantoin, pivmecillinam, trimethoprim with sulphonamides, and penicillins with enzyme inhibitor and macrolides. The increase of pivmecillinam and nitrofurantoin is in accordance with national treatment recommendations since they are recommended as first line antibiotics for urinary tract infections (UTIs). A shortage of erythromycin during the spring of 2013 affected the statistics and explains the increased sales of macrolides in 2014. Beta-lactamase–sensitive penicillins together with tetracyclines were the most commonly used antibiotics in outpatient care. Antibiotics commonly used to treat respiratory tract infections were the most frequently prescribed antibiotics. Among these substances, we also found the greatest decrease in sales (7 percent) in 2014 compared to 2013. The decrease is mainly related to a significant reduction in sales of beta-lactamase– sensitive penicillins (8 percent) and tetracyclines (10 percent). Treatment of lower UTIs in women appears to be following national recommendations. In 2014, the total sales of antibiotics commonly used to treat UTIs in women aged 18–79 years decreased slightly (1 percent) compared to 2013. The same positive trend as previously described with increased use
of the first-line drugs pivmecillinam and nitrofurantoin and reduced sales of trimethoprim (13 percent) and fluoroquinolones (2 percent) was seen. The total sales of antibiotics commonly used to treat UTIs in men 65 years and older increased slightly (1 percent) in 2014 compared to 2013. Fluoroquinolones are still the most common antibiotics for treating UTIs in this population, but sales of fluoroquinolones decreased by 2 percent in 2014 compared to 2013. In 2014, the sales of pivmecillinam and nitrofurantoin increased by 20 percent and 12 percent, respectively, as measured by prescriptions per 1 000 men and year, compared to 2013. The sales of antibiotics prescribed by dentists decreased by 9 percent in 2014 compared to 2013, from 26.0 to 23.6 prescriptions per 1 000 inhabitants and year for J01 and metronidazole (P01AB01). The greatest decrease in 2014 was seen for amoxicillin (13 percent) and clindamycin (14 percent). In 2014, the total consumption of antibiotics in Swedish acute care hospitals increased slightly compared to 2013. The consumption of beta-lactamase–sensitive penicillins, cephalosporins, and aminoglycosides did not change during the last year, and the consumption is at almost the same level as in 2013. The use of beta-lactamase–resistant penicillins, fluoroquinolones, penicillins with enzyme inhibitor and carbapenems continues to increase as in previous years. Penicillins with enzyme inhibitor have increased significantly in recent years, and carbapenems have increased marginally, these agents have replaced the cephalosporins in many situations. In 2014, penicillins with enzyme inhibitor increased by 7.3 percent when measured as DDD per 100 patient-days compared to 2013. The increase is probably a result of an increased number of infections with ESBL (Extended spectrum beta-lactamase). The percentage of broad-spectrum antibiotics (fluoroquinolones, cephalosporins, piperacillin with tazobactam, and carbapenems) out of all antibiotics in Swedish acute care hospitals varied from 28.6 percent in Värmland County to 37.6 percent in Östergötland County. When analyzing the total antibiotic consumption in hospitals (including all hospitals and parts of nursing homes and other care units) from 2000–2014, a clear shift from high use of broad-spectrum antibiotics to narrow-spectrum antibiotics can be seen.
Sales of antifungals Compared to 2013, the total consumption of antifungal drugs for systemic use has remained unchanged with a national average of 61 DDD per million inhabitants and day. Every year since 2000, except for 2011 and 2014, there has been a small but steady increase in the total consumption of antifungals. Since the year 2000 when the total consumption was 40 DDD per million inhabitants and day, the increase has been 50 percent. Fluconazole still constitutes the absolute majority of the antifungals used at 65 percent or 39.5 DDD per million inhabitants and day. Amphotericin B is the second most used compound. The sales of amphotericin B increased by 28 percent compared to 2013 and now accounts for 16 percent of the total consumption.
SWEDRES | SVARM 2014
Since 2005, there has been a small but steady increase in the consumption of the echinocandins. In 2014, consumption increased by 11 percent bringing the total amount to 7.3 DDD per million inhabitants and day, and the group now constitutes 12 percent of all systemic antifungal consumption in hospital care. The consumption of caspofungin, which has been available in Sweden since 2002, has decreased every year. It now constitutes 44 percent of the echinocandins down from 60 percent in 2013. Anidulafungin increased its share from 30 percent to 38 percent last year. The third member of the group, micafungin, that appeared for the first time in the statistics in 2012 now constitutes 18 percent of the total echinocandin consumption. Many of the counties with tertiary care hospitals have largely increased their use of both anidulafungin and micafungin at the expense of caspofungin.
Consumption of antibiotics in animals There are indications that the data on sales from Swedish pharmacies are less complete than before the reregulation of the Swedish pharmacy market in 2009. This problem probably mainly affects the sales of antibiotics for parenteral use, but because such drugs make up at least 70 percent of the overall consumption the magnitude of overall trends from 2010 cannot be assessed with certainty. The overall consumption of antimicrobials has decreased gradually since the mid-1990s, and there has also most likely been a true decrease since 2010. Products for oral medication of individual animals and oral medication of groups of animals via feed or water are less likely to be affected by the lack of completeness in the data. Major downward trends are noted from 2010 to 2014 for both of these categories (by 32 percent and 55 percent, respectively).
Comparing sales for humans and animals In 2014, a total of 60.5 tons and 10.2 tons of antibiotics were consumed in human and veterinary medicine, respectively. When measured as mg active substance per kg estimated biomass, the corresponding figures were 96.4 mg per kg and 12.7 mg per kg. Consumption in human medicine by far outweighs consumption in veterinary medicine for most classes except for trimethoprim-sulphonamides and aminoglycosides.
Notifiable resistance ESBL-producing Enterobacteiaceae A total of 8 902 human cases of extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae were reported in 2014, and this corresponds to an incidence of 91 cases per 100 000 inhabitants. This is an increase of 9 percent compared to 2013, and increases occurred in 15 counties. The most commonly reported species was Escherichia coli with 89 percent of all cases followed by Klebsiella pneumoniae with 7 percent. Most ESBL-producing bacteria were found in urine samples (59 percent). Invasive infections with ESBL-producing bacteria increased from 402 cases in 2013 to 520 cases in 2014. A special type of ESBLs, so-called ESBLCARBA, constitute a broader mechanism. Bacteria with this extended resistance
mechanism became notifiable from both clinicians and laboratories in 2012. Forty-six new cases were detected in 2014, and the two most common types of enzymes were OXA-48 and NDM. Two domestic transmissions involving four persons were reported in 2014, one occurred in a hospital and the other in care outside a hospital. Because the treatment alternatives for these infections are few if any, it is necessary to have an active surveillance of these new and extremely resistant bacteria in order to detect them at an early stage and thereby hinder their spread within the health care system. In animals, ESBL-producing Enterobacteriaceae occurs both as gut colonization and as clinical isolates, mainly from wounds or from the urogenital tract. The occurrence is relatively low, with the exception of broilers were ESBL-producing E. coli is isolated from a large proportion of the caecal samples. However, there has been a significant decrease in the occurrence in broilers and the proportion of positive samples is now comparable to the situation in 2010 when the problem was first discovered.
MRSA The total number of human cases of methicillin-resistant Staphylococcus aureus (MRSA) was 2 921 in 2014, an increase of 19 percent compared to 2013. According to the systematically reviewed notification reports, infections were as often acquired in Sweden as abroad. Community-acquired infections dominated among domestic cases (76 percent) but were less frequent among imported cases (50 percent). Hospital-acquired infections were comparatively more common in imported cases (28 percent) than among domestic cases (8 percent), indicating continued good compliance to basic hygiene principles among healthcare staff in Sweden. Thirty-nine invasive isolates of MRSA were reported in 2014. Epidemiological typing of isolates by spa-typing showed that the five most commonly encountered spa-types in 2014 were t223, t008, t044, t002, and t127. The prevalence of MRSA with PVL toxin had decreased to 35 percent. The occurrence of MRSA in animals in Sweden is still low, and this limits the spread from animals to humans. In 2014, MRSA was not detected in a screening of nucleus and multiplying pig herds. MRSA was found sporadically in horses, dogs, cats, cattle, and hedgehogs in 2014. In companion animals, the same types of MRSA as in humans dominate indicating a human source of MRSA in these animals. In horses, livestock-associated MRSA CC398 is most common.
MRSP In 2014, 39 cases of methicillin-resistant Staphylococcus pseudintermedius (MRSP) were reported in dogs (36 cases), cats (2 cases), and horses (1 case). The number of cases reported yearly has declined since 2009 when 130 cases were reported. No human cases were reported in 2014, but MRSP in humans is not generally notifiable to the authorities.
PNSP In 2012, the definition for Streptococcus pneumoniae with reduced susceptibility to penicillin (PNSP) was changed to include only isolates with an MIC (minimal inhibitor concentration) of
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penicillin > 1 mg/L, and this resulted in a dramatic decrease in reported cases. A total of 70 new cases of PNSP were reported in 2014. In order to follow and evaluate the effect of vaccination against pneumococcal disease, The Public Health Agency of Sweden has continued to collect and perform serotyping on PNSP isolates according to the previous definition (MIC ≥ 0.5 mg/L). The most commonly encountered serotypes in 2014 were 19F, NT, 35B, 19A, 23F, 14, 11A, 6B, and 9V.
VRE In 2014, a total of 402 new cases of vancomycin-resistant enterococci (VRE) were reported, which was an increase of 77 percent compared to 2013. The majority of isolates were Enterococcus faecium, and in contrast to 2013 isolates with the resistance gene vanB outnumbered those with the vanA gene. Thirteen healthcare-related outbreaks were reported from six counties, all with E. faecium, and seven carried the vanA gene and six carried the vanB gene. The largest outbreak, in Gävleborg County, started in September 2013 and ended at the end of 2014 and comprised approximately 314 cases.
Zoonotic pathogens Salmonella is rare in animals in Sweden, and few incidents involve antibiotic-resistant strains. Strains with ESBLresistance have never been found, and resistance to fluoroquinolones is rare. Invasive infections in humans are mainly caused by other Salmonella serovars than those found in animals and isolates are often quinolone resistant. Animals in Sweden is therefore an unlikely source of Salmonella causing these infections. Campylobacter from animals in Sweden are mostly susceptible, and for example resistance to erythromycin is most uncommon. Animals in Sweden are, therefore, an unlikely source for the highly resistant Campylobacter seen in isolates from humans. Infections caused by Salmonella or Campylobacter are usually not treated with antibiotics, neither in humans nor in animals. In humans, this means that data on antibiotic resistance is mainly available from a small number of invasive infections.
Human clinical isolates EARS-Net surveillance Invasive isolates of eight bacterial species have been reported to EARSS/EARS-Net. In 2014, seven laboratories reported data on all positive blood cultures. Escherichia coli was the most frequently found pathogen in blood cultures at 26.4 percent followed by S. aureus at 13.4 percent. The six other pathogens in the EARS-Net system were all much less frequently found. In E. coli and K. pneumoniae, the levels of resistance to third-generation cephalosporins had increased to 5.4 and 4.0 percent, respectively. MRSA isolates accounted for 0.9 percent of all invasive S. aureus, which is low from a European perspective. The rates of non-susceptibility to penicillins in S. pneumoniae (referred to as PNSP) was higher than in previous years at 6.4 percent in 2014. There were still no VRE reported for E. faecalis in 2014, and the level
was at 0.7 percent among invasive isolates of E. faecium (3 cases), but high-level resistance to aminoglycosides (HLAR) was common at 15.6 percent and 22.5 percent in E. faecalis and E. faecium, respectively.
National surveillance and quality assurance programme, ResNet The same bacterial species as in EARS-Net are part of the ResNet programme, but samples from UTIs (E. coli and K. pneumoniae), skin and soft tissue infections (S. aureus), respiratory tract infections (S. pneumoniae and H. influenzae), or all sources (P. aeruginosa) are also included in the ResNet programme. In general, the same rates of resistance were found in these two programmes. Other bacterial species are included in special surveillance programmes and are often referred to special laboratories. These species include Clostridium difficile and Mycobacterium tuberculosis (The Public Health Agency of Sweden) and Neisseria gonorrhoeae and N. meningitidis (National Reference Laboratory in Örebro). The proportion of C. difficile isolates resistant to the indicator antibiotics erythromycin and clindamycin increased slightly in 2014, while that of moxifloxacin was the same as in 2013. Ribotype type 027 increased in 2014 due to the outbreak in Kronoberg (separate report). In 2014, the resistance in gonococci to cefixime (2 percent) continued to decrease, and the resistance to ceftriaxone (0.3 percent) remained low. This is promising because ceftriaxone is the last remaining option for empirical antimicrobial monotherapy of gonorrhoea. Rates of resistance to antituberculosis drugs in M. tuberculosis are carefully monitored, and the situation is good.
Animal clinical isolates Bacteria causing clinical disease in animals are mostly susceptible to antibiotics relevant for treatment. Respiratory pathogens from farm animals and horses are generally susceptible to bensylpenicillin, but penicillin resistance is common in S. pseudintermedius from dogs and it occurs in S. aureus from horses and Staphylococcus felis from cats. Resistance in E. coli occurs in all animals but is most prominent in enteric isolates from young calves. Susceptibility testing for guidance in antibiotic therapy is warranted, especially for staphylococci and E. coli.
Indicator bacteria from healthy animals Antibiotic resistance in E. coli, E. faecalis, and E. faecium from the intestinal flora of healthy animals serves as an indicator for the presence of resistance in an animal population. Also, the prevalence of acquired resistance in such commensal bacteria indirectly indicates the magnitude of the selective pressure from the use of antibiotics in an animal population. Prevalence of resistance in indicator bacteria from animals in Sweden is low, and the situation is favorable in an international perspective.
SWEDRES | SVARM 2014
Guidance for readers The Swedres-Svarm report is the result of cooperation between the Public Health Agency of Sweden and the National Veterinary Institute with the aim to present data relating to both humans and animals on the use of antibiotics and on antibiotic resistance in a joint report. Data on occurrence of notifiable diseases caused by resistant bacteria as well as data on resistance in zoonotic bacteria and in bacteria from clinical submissions is presented. In addition, data on resistance in so called indicator bacteria from healthy animals and from food of animal origin is presented. Data on resistance in bacteria from humans is obtained from several sources and national programs and compiled by the Public Health Agency of Sweden in Swedres. In contrast, data on animals and food, compiled by the National Veterinary Institute, is from the national monitoring program in the veterinary field Svarm. This program is specifically designed to monitor resistance in bacteria from animals and food and is organized and run at the National Veterinary Institute. Data in the veterinary field also emanate from other sources, such as the Svarmpat project and specific research projects. For details on data sources see Background material and references.
of the Clinical and Laboratory Standards Institute (CLSI, 2014). MICs for isolates of zoonotic and indicator bacteria are interpreted by ECOFFs from EUCAST (www.eucast. org) and also clinical isolates from animals are classified by ECOFFs when such values are available. Interpretive criteria used are given in the section Materials and methods, resistance in bacteria from animals. ECOFFs classify isolates with acquired reduced susceptibility as non-wild type. In Svarm, non-wild type isolates are called “resistant”. This classification is relevant for monitoring purposes, but it should be understood that resistance defined in this manner not always implies clinical resistance. Since the first report from Svarm, some interpretive criteria (ECOFFs) have been changed by EUCAST. To facilitate comparisons when retrospect data is presented, levels of resistance have been recalculated using current interpretive criteria if not otherwise stated.
Indicator bacteria in Svarm In Svarm, Escherichia coli, Enterococcus faecalis and E. faecium serve as indicators for presence of antibiotic resistance in the enteric flora of healthy animals and in the flora contaminating food. The prevalence of acquired resistance in such commensal bacteria in animals indicates the magnitude of the selective pressure from use of antibiotics in an animal population. Most bacteria of the enteric flora are unlikely to cause disease, but they can be reservoirs for resistance genes that can spread to bacteria that cause infections in animals or humans. Prevalence of resistance in indicator bacteria contaminating meat indicates the magnitude of the potential human exposure to such reservoirs in food producing animals.
Antibiotic resistance Swedres Most of the data on resistance in Swedres is derived from routine diagnostic samples sent for testing at clinical laboratories. The results are mostly presented as proportion resistance in tables or graphs. The methods used for antibiotic susceptibility testing, whether MIC determination or disk diffusion inhibition zones, are standardized by European Committee on Antimicrobial Susceptibility Testing (EUCAST) and available online at www.eucast.org. EUCAST also presents yearly updated interpretative criteria for clinical use in human medicine, i.e. clinical breakpoints, also available at www. eucast.org. In Swedres, only MIC results for Clostridium difficile were interpreted using ECOFFs.
Presentation of MIC distributions in Svarm Results from MIC determinations in Svarm are presented as distributions of MICs in tables of a uniform design as below. Distributions are given as percentages of isolates tested. In the tables, white fields denote range of dilutions tested for each antibiotic and vertical bold lines indicate cut-off values used to define resistance. The percentage of isolates with a certain MIC of an antibiotic is given in the corresponding white field. For MICs above the range tested of an antibiotic (>X mg/L) the percentage is given in the field closest to the range, i.e. in the
Svarm The vast majority of data on resistance in Svarm is from MIC determinations performed at the National Veterinary Institute using broth microdilution following the standards
Example of a table with MIC distributions Antibiotic
Resistance
Distribution (%) of MICs (mg/L)
(%)
≤0.06
0.12
0.25
Ciprofloxacin
21
21.0
52.0
6.0
Erythromycin
0
Tetracycline
2
75.0
22.0
0.5
1
2
93.0
4.0
3.0
4
8
1.0
1.0
16 20.0
1.0
1.0
32
64
>64
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Abbreviations of generic antibiotic names When abbreviations for antibacterials were needed in tables or graphs the following were used. Amp
Ampicillin
Ery
Erythromycin
Oxa
Oxacillin
Bac
Bacitracin
Flf
Florfenicol
Pen
Penicillin G
Caz
Ceftazidim
Fox
Cefoxitin
Rif
Rifampicin
Cdr
Cefadroxil
Fus
Fusidic acid
Str
Streptomycin
Cer
Ceftiofur
Gen
Gentamicin
Sul
Sulphonamide
Cet
Cephalothin
Imp
Imipenem
Tet
Tetracycline
Chl
Chloramphenicol
Kan
Kanamycin
Tmp
Trimethoprim
Cip
Ciprofloxacin
Lin
Linezolid
Tsu
Trimethoprim-sulfonamide
Cli
Clindamycin
Mec
Mecillinam
Tob
Tobramycin
Col
Colistin
Mer
Meropenem
Van
Vancomycin
Ctx
Cefotaxim
Nal
Nalidixic acid
Vir
Virginiamycin
Enr
Enrofloxacin
Nar
Narasin
first shaded field to the right of the tested range. For MICs equal to or lower than the lowest concentration tested for an antibiotic (≤Y mg/L) the percentage is given as the lowest tested concentration, i.e. in the first white field of the tested range.
Multidrug resistance The terms multidrug resistance (MDR), multiresistance and multiresistant are in Svarm used for isolates with phenotypically identified acquired resistance to three or more antibiotic classes. This implies, for example, that resistance to ciprofloxacin, enrofloxacin and nalidixic acid represents resistance to one class of antibiotics.
Antibiotic consumption Antibacterials for systemic use in human are indexed as J01 in the Anatomical Therapeutic Chemical classification system. Unfortunately, the J01 group also includes the antiseptic substance methenamine. This is not an antibiotic and has no influence on antibiotic resistance. Throughout this report, methenamine is consequently excluded whenever antibiotics are referred to or presented. In this report the term antibiotic is used. However the report also includes a chapter regarding sales of antifungals (J02).
Comparison of consumption of antibiotics between counties and to elderly people over time is complicated by the fact that there are differences in how medicines are distributed to residents in nursing homes. In Sweden, most people living in nursing homes still get their medicines by prescription, and data on this consumption is included in outpatient care data. However, there are also nursing homes where medicines are bought by the institution and then dispensed to the residents. Such consumption is included in hospital care data. Since routines differ between counties and over time, the appraisal of antibiotic use to elderly people is not entirely reliable. Wherever sales of antibiotics to a certain group of people is displayed (children 0-6 years, women 18-79 years, inhabitants in a county), the denominator is the number of individuals in the same group. In this report the term outpatient care includes all antibiotic sales on prescriptions. Hospital care includes antibiotic sales on hospital requisition (including hospitals, parts of nursing homes and other care units). Since national data on antibiotic consumption in hospitals in Sweden are aggregated with sales to some nursing homes, this is not suitable for evaluation of antibiotic use in hospital care. Therefore, data on sales exclusively to acute care hospitals has been provided by pharmacists in local Strama groups in all counties. Treatment recommendations are adopted locally by the county drug and therapeutics committee, and therefore the prescribed daily doses for certain indications can vary between counties. This should be kept in mind, as it may affect the comparisons based on the statistics.
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Abbreviations ATC
Anatomical therapeutic chemical classification system
BLNAR
Beta-lactamase negative ampicillin resistant (in Haemophilus influenzae)
CC
Clonal cluster, used in the context of epidemiological typing
CDI
Clostridium difficile infection
CMO
County medical officer
DDD
Defined daily dose
ECDC
European Centre for Disease Prevention and Control
ECOFF
Epidemiological cut-off value for non-susceptibility
EARSS/EARS-Net
European antimicrobial resistance surveillance system/network
ESC
Extended spectrum cephalosporin
ESBL
Extended spectrum beta-lactamase
ESBLA
Extended spectrum beta-lactamase, plasmid-mediated, inhibited by clavulanic acid (A = classical)
ESBLM
Extended spectrum beta-lactamase inhibited by cloxacillin, also called plasmid-mediated AmpC (M = miscellaneous)
ESBLCARBA
Extended spectrum beta-lactamase with activity against carbapenems
EUCAST
European Committee on Antimicrobial Susceptibility Testing
GAS
Group A streptococci or Streptococcus pyogenes
GBS
Group B streptococci or Streptococcus agalactiae
HLAR
High-level aminoglycoside resistance (e.g. in Enterococcus)
MDR
Multidrug resistance, i.e. phenotypic resistance to three or more antibiotic classes
MIC
Minimal inhibitory concentration
MLST
Multilocus sequence typing
MRB
Multi-resistant bacteria
MRSA
Methicillin-resistant Staphylococcus aureus
MRSP
Methicillin-resistant Staphylococcus pseudintermedius
NordicAST
Nordic Committee on Antimicrobial Susceptibility Testing
PFGE
Pulsed-field gel electrophoresis
PNSP
Penicillin non-susceptible pneumococci
PVL
Panton-Valentine leukocidin
ResNet
Webb application for Resistance surveillance and quality control programme
RTI
Respiratory tract infection
spa
Staphylococcal protein A
SSTI
Skin and soft tissue infection
ST
Sequence type
Strama
Swedish strategic programme against antibiotic resistance
Svarm
Swedish antibiotic resistance monitoring program
TB
Tuberculosis
UTI
Urinary tract infection
VRE
Vancomycin resistant enterococci
XDR
Extreme drug resistance (used for Mycobacterium tuberculosis)
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Consumption of antimicrobials Total consumption of antibiotics in humans In 2014, the total consumption of antibiotics (J01 excl. methenamine) in Sweden (outpatient care and hospital care) decreased by 4% compared with 2013 (13.4 to 12.8 DDD per 1 000 inhabitants and day). The overall consumption has decreased by 11% since 2000, from 14.5 to 12.8 DDD per 1 000 inhabitants and day, Table 1.1. Eighty-seven percent of all antibiotic sales in Sweden 2014 were sold on prescriptions in outpatient care as indicated in Figure 1.1. This proportion vary within the country, from 90% in Halland County to 83% in Kronoberg County.
Even though the majority of all antibiotics is prescribed in outpatient care, data from the Swedish Association of Local Authorities and Regions point prevalence survey in the spring of 2014, indicated that 35.3% of all inpatients were treated with an antibiotic on a specific day, this figure exclude patients in psychiatric care (the Swedish Association of Local Authorities and Regions, 2014). Beta-lactamase sensitive penicillins and tetracyclines were the two most used antibiotic classes in Sweden during 2014, Figure 1.2.
Table 1.1. Consumption of antibiotics in outpatient care (sales on prescriptions) and in hospital care (sales on requisition including hospitals and parts of nursing homes) in Sweden, 2000-2014, DDD/1 000 inhabitants and day. 2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
J01 exclusive J01XX05
Total
14.5
14.7
14.4
14.4
14.1
14.6
15.0
15.4
15.2
14.4
14.3
14.5
14.2
13.4
12.8
J01 exclusive J01XX05
Outpatient care
13.1
13.3
13.0
12.8
12.6
13.0
13.3
13.7
13.5
12.8
12.7
12.8
12.5
11.7
11.2
J01 exclusive J01XX05
Hospital care
1.18
1.22
1.25
1.33
1.36
1.43
1.49
1.55
1.52
1.48
1.52
1.59
1.63
1.60
1.60
J01XX05
Total
1.56
1.55
1.64
1.72
1.86
1.88
1.88
1.81
1.60
1.43
1.33
1.28
1.27
1.24
1.22
J01XX05
Outpatient care
1.48
1.49
1.60
1.67
1.78
1.80
1.81
1.74
1.55
1.40
1.30
1.26
1.25
1.22
1.20
J01XX05
Hospital care
0.03
0.03
0.03
0.05
0.07
0.07
0.07
0.07
0.05
0.03
0.03
0.02
0.02
0.02
0.02
J01
Total
16.1
16.3
16.1
16.1
16.0
16.5
16.9
17.3
16.8
15.8
15.7
15.7
15.5
14.7
14.1
J01
Outpatient care
14.6
14.8
14.6
14.5
14.3
14.8
15.1
15.4
15.1
14.2
14.0
14.0
13.8
13.0
12.4
J01
Hospital care
1.21
1.25
1.27
1.37
1.43
1.50
1.56
1.62
1.57
1.52
1.55
1.61
1.65
1.62
1.62
Figure 1.2. Antibiotics (ATC-5) in outpatient care (sales on prescriptions) and hospital care (sales on requisition including hospitals and parts of nursing homes) in 2014, DDD/1 000 inhabitants and day. Carbapenems (J01DH)
16
Trimethoprim (J01EA)
14
Cephalosporins (J01DB-DE)
12
Macrolides (J01FA)
10
Trimethoprim with sulphonamides (J01EE)
8
Combinations of penicillins (J01CR)
6
Lincosamides (J01FF)
4
Nitrofurantoin (J01XE)
2
Pivmecillinam (J01CA08)
0
St o
ck h U olm pp s Sk ala å Ö ne Vä st B reb l ra ek ro Vä Gö ing st tala e m n an d G lan o d K Sö ro tlan de no d rm be a rg Vä nla rm nd Ö H land st al er la gö nd tla K n N almd or rb ar o D tten a Vä Gä lar st vle na er b Vä nor org st rla er nd Jö bot nk te n Jä öpi m ng tla nd
DDD/1000 inhabitants and day
Figure 1.1. Consumption of antibiotics (J01 excl. methenamine) in outpatient care (sales on prescriptions) and in hospital care (sales on requisition including hospitals and parts of nursing homes) per county, 2014, DDD/1 000 inhabitants and day.
Outpatent care
Hospital care
Fluoroquinolones (J01MA) Penicillins with extended spectrum (J01CA) excl. pivmecillinam (J01CA08) Betalactamase-resistant penicillins (J01CF) Tetracyclines (J01A) Betalactamase sensitive penicillins (J01CE) 0
0,5
1
1,5
2
2,5
3
3,5
DDD/1000 inhabitants and day Outpatient care
Hospital care
4
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SWEDRES | SVARM 2014
Antibiotics in outpatient care Note that the statistics for outpatient care reported in Swedres-Svarm includes all sales of antibiotics on prescriptions, both from healthcare centers as well as prescriptions from hospital care.
1400 1200 1000 800 600 400 200 0
1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Prescriptions/1000 inhabitants and year
Figure 1.3. The sales of antibiotics for systemic use in out-patient care (sales on prescriptions) 1987- 2014, prescriptions/1 000 inhabitants and year, both sexes, different age groups. The sales in 2014 decreased in all age groups.
0-4
5 - 14
15 - 64
65* -
All age groups
*1987-2000 includes antibiotic sale to people aged 65-99 years. From 1999. the statistic includes antibiotic sale on Apo-Dose.
Sales of antibiotics in outpatient care has continued to decrease (4%) during 2014, from 343 in 2013 to 328 prescriptions per 1 000 inhabitants and year. The decrease in 2014 was seen in all age groups and is most evident in the age group 5-14 years (8%), Figure 1.3. Since 1992, the total sales of antibiotics on prescriptions has decreased by 41%. The greatest decrease during
these years has been in the 0-4 years age group, where sales decreased by 71%, from 1328 in 1992 to 328 prescriptions per 1 000 inhabitants and year in 2014. The age group 65 years and older had the highest use of antibiotics in Sweden, as measured by prescriptions per 1 000 inhabitants and year, Figure 1.3. As mentioned in the chapter “Guidance for readers”, some of the antibiotic use among elderly people is not included in the statistics for outpatient care and possible underestimate in the age group 65 years and older cannot be ruled out. The decrease in antibiotics sales in outpatient care during 2014 encompasses all but nitrofurantoin (J01XE), penicillins with enzyme inhibitor (J01CR), trimethoprim with sulphonamides (J01EE), macrolides (J01FA) and pivmecillinam (J01CA08), Figure 1.4. Beta-lactamase sensitive penicillins (J01CE) and tetracyclines (J01AA) were the most commonly sold antibiotics in 2014, Figure 1.4 and Table 1.2. In 2014, the sales of betalactamase sensitive penicillins decreased by 8% and tetracyclines by 10% compared with 2013. Doxycycline (J01AA02) is the most frequently sold tetracycline and represents 72% of the sales in this group as measured by prescriptions per 1 000 inhabitants and year. Trimethoprim (J01EA) is the antibiotic group with the proportionally greatest decrease during 2014 compared with 2013 (13%), Figure 1.4. Trimethoprim is mostly used to treat lower urinary tract infections. The decrease in sales of trimethoprim is seen in both sexes in the same amount (13% in both sexes). In summary, a great decrease in the sales are seen in most of the antibiotic groups during 2014, Figure 1.4 and Table 1.2. Possible explanations for the change in the sales during 2014 will be discussed in following chapters.
Figure 1.4. Sales of antibiotics in outpatient care (includes sales on prescriptions) 2000-2014, prescriptions/1 000 inhabitants and year, both sexes, all ages. The data are sorted according to ATC codes.
Prescriptions /1000 inhabitants and year
160,0 140,0 120,0 100,0 80,0 60,0 40,0 20,0
1C
A-
J0 1A A
-T et Pe ra cy sp nic cl ec illin in tru s es m wi t ex h e cl x . J te J0 01 nd 1C CA ed A0 08 J0 8 1C -P E i vm -B ec et illi al ac na t m am J0 as 1C e F s -B pe ens et ni itiv al ci e ac llin ta J0 s m 1C as R e-C re pe sis om ni ta bi ci nt na llin tio s J0 ns 1D of B p en -J ici 01 llin D E s -C ep ha lo sp or J0 in 1E s A -T rim et J0 ho 1E pr w Eim ith T r su im lp et ho ho na pr m im id J0 es 1F A -M ac ro J0 lid 1F es F -L in co J0 sa 1M m A id es -F lu or oq ui no lo J0 ne 1X s E -N itr J0 of 1X ur X an -O to in th er an tib ac te ria ls
0,0
J0
18
2000
2005
2007
2008
2009
2010
2011
2012
2013
2014
SWEDRES | SVARM 2014
Figure 1.5. Sales of antibiotics (J01 excl. methenamine) in outpatient care (sales on prescriptions) in different age groups. Measured by both prescriptions/1 000 inhabitants and year and as DDD/1 000 inhabitants and day, in 2014. 25 20
600 500
15
400 10
300 200
5
85 - 89 years 90 - years
75 - 79 years 80 - 84 years
70 - 74 years
65 - 69 years
55 - 59 years 60 - 64 years
50 - 54 years
45 - 49 years
40 - 44 years
35 - 39 years
25 - 29 years 30 - 34 years
15 - 19 years
20 - 24 years
5 - 9 years
0
Age groups Prescriptions / 1000 inhabitants
DDD / 1000 inhabitants and day
Gender differences Out of all antibiotic prescribed in Sweden during 2014, 60% were prescribed to females and 40% to males. This proportion has almost been constant over time and the decrease in antibiotic sales during the last years has been seen in both sexes equally. During 2014, the antibiotic sales decreased by 4% in men and 3% in women. The greatest differences between genders occurred in the age group 20-39 years were 65-70% of the total antibiotic sales were to women. In this age group the main differences is among antibiotics commonly used to treat urinary tract infections (UTI) which are predominant sold to women. Read more about gender differences in antibiotic sales in SWEDRES 2011 (Swedres-Svarm 2011).
Figure 1.6. Antibiotics commonly used to treat: respiratory tract infections (J01AA02*, J01CE02, J01CA04, J01CR02, J01DB-DE and J01FA), urinary tract infections (J01CA08, J01EA01, J01MA02, J01MA06 and J01XE01), skin and soft tissue infections (J01FF01 and J01CF05), acne (J01AA02**, J01AA04, J01AA06 and J01AA07), both sexes, different age groups, prescriptions in 2014.
The antibiotic use is greatest in the age groups 65 years and older, both as measured by prescriptions/1 000 inhabitants and years and by DDD/1 000 inhabitants and day, Figure 1.5. However, even though the antibiotic use is high among children and elderly, other age groups represent a significant share of the total antibiotic sales, Figure 1.6. Figures 1.6 and 1.7 illustrate the sales of different antibiotics in different age groups. In children, antibiotics commonly used to treat respiratory tract infections (RTI) are the most frequently prescribed antibiotics and represents 90% of the total antibiotic sales. In the older age groups antibiotic commonly used to treat UTI are as common as antibiotics commonly used to treat RTI. In contrast, in the age group 15-19 years, antibiotics commonly used to treat acne represent a larger proportion. This kind of antibiotics are prescribed with long treatment duration, hence the peak seen in Figure 1.5 for this age group measured as DDD per 1 000 inhabitants and day.
Antibiotics commonly used to treat treat respiratory tract infections Antibiotics commonly used to treat respiratory tract infections (RTI) are overall the most frequently prescribed antibiotics in Sweden. Among these substances we also find the greatest decrease in sales during 2014 (7%), as well as over time in terms of number of prescriptions per 1 000 inhabitants and year, from 294 in 2000 to 166 in 2014.
Figure 1.7. Antibiotics commonly used to treat: respiratory tract infections (J01AA02*, J01CE02, J01CA04, J01CR02, J01DB-DE and J01FA), urinary tract infections (J01CA08, J01EA01, J01MA02, J01MA06 and J01XE01), skin and soft tissue infections (J01FF01 and J01CF05), acne (J01AA02**, J01AA04, J01AA06 and J01AA07), both sexes, different age groups, prescriptions/1 000 inhabitants in 2014. 800 Prescriptions/1000 inhabitants
300000
200000 150000 100000 50000
600 500 400 300 200 100 90 - years
85 - 89 years
80 - 84 years
75 - 79 years
70 - 74 years
65 - 69 years
60 - 64 years
55 - 59 years
50 - 54 years
45 - 49 years
40 - 44 years
35 - 39 years
30 - 34 years
25 - 29 years
20 - 24 years
15 - 19 years
5 - 9 years
90 - years
85 - 89 years
80 - 84 years
70 - 74 years
75 - 79 years
65 - 69 years
60 - 64 years
55 - 59 years
50 - 54 years
45 - 49 years
40 - 44 years
35 - 39 years
30 - 34 years
25 - 29 years
20 - 24 years
15 - 19 years
10 - 14 years
5 - 9 years
0 0 - 4 years
0
700
0 - 4 years
Prescriptions
250000
10 - 14 years
0
10 - 14 years
100
In different age groups DDD/1000 inhabitants and day
700
0 - 4 years
Prescriptions/1000 inhabitants
800
Antibiotics commonly used to treat respiratory tract infections, urinary tract infections and skin and soft tissue infections
Antibiotics commonly used to treat respiratory tract infections
Antibiotics commonly used to treat urinary tract infections
Antibiotics commonly used to treat respiratory tract infections
Antibiotics commonly used to treat urinary tract infections
Antibiotics commonly used to treat skin and soft tissue infections
Antibiotics commonly used to treat acne
Antibiotics commonly used to treat skin and soft tissue infections
Antibiotics commonly used to treat acne
*Excluding packages containing more than 50 tablets. ** Including packages containing more than 50 tablets.
*Excluding packages containing more than 50 tablets. ** Including packages containing more than 50 tablets.
19
20
SWEDRES | SVARM 2014
Table 1.2. Antibiotics in outpatient care, classes of antibiotics and age groups. DDD/1000 inhabitants and day, prescriptions/1000 inhabitants and year and user/1000 inhabitants and year. DDD/1000 and day Age groups (years)
Prescriptions/1000 and year
User/1000 and year
2007 2008 2009 2010 2011 2012 2013 2014 2007 2008 2009 2010 2011 2012 2013 2014 2007 2008 2009 2010 2011 2012 2013 2014 Tetracyclines (J01AA)
0-6
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.0
0.0
0.0
0.0
0.1
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.1
0.0
0.0
0.0
7-19
3.23
3.25
3.31
3.40
3.48
3.29
3.06
2.82
33.9
32.0
31.6
32.5
35.1
31.2
27.6
25.1
21.3
19.5
19.2
20.1
22.9
19.6
16.8
15.5
20-64
3.77
3.56
3.30
3.35
3.54
3.43
3.10
2.92
71.9
64.5
56.2
56.3
60.2
56.5
47.7
43.1
56.3
50.3
43.6
43.8
47.2
43.8
36.4
32.9
65-79
4.21
3.99
3.64
3.60
3.78
3.75
3.36
3.06
98.8
90.6
79.9
78.0
81.1
80.0
68.9
60.4
75.4
68.8
61.2
60.1
62.1
61.3
52.5
46.2
80-
2.93
2.77
2.43
2.32
2.35
2.41
2.15
1.97
77.8
71.7
62.2
58.6
58.8
59.8
52.5
45.7
62.1
57.1
49.7
46.8
47.2
47.7
41.9
36.3
All age groups
3.44
3.28
3.08
3.11
3.25
3.15
2.85
2.66
64.3
58.3
51.7
51.6
54.7
52.0
44.4
39.8
49.0
44.1
38.8
38.9
41.7
39.2
33.1
29.8
42.1
33.6
33.5
Penicillins with extended spectrum (J01CA) excl. Pivmecillinam (J01CA08) 0-6
1.74
1.70
1.52
1.62
1.35
1.32
1.07
1.08
95.2
90.8
72.7
73.3
59.1
54.9
7-19
0.46
0.43
0.39
0.43
0.43
0.37
0.32
0.31
14.5
13.6
11.8
12.4
12.0
10.1
20-64
0.84
0.82
0.72
0.73
0.69
0.64
0.59
0.56
21.2
20.6
18.2
18.0
16.9
15.4
65-79
1.74
1.75
1.67
1.62
1.59
1.55
1.50
1.44
45.6
45.0
41.7
40.2
38.7
37.0
80-
1.79
1.82
1.76
1.74
1.75
1.77
1.73
1.71
46.8
46.5
44.0
42.1
41.0
39.7
All age groups
1.02
1.01
0.93
0.94
0.89
0.85
0.79
0.76
31.0
30.5
26.9
26.9
24.4
22.7
43.8
43.7
72.5
69.0
56.5
57.4
45.3
8.5
8.2
12.7
11.7
10.1
10.6
10.1
8.3
6.9
6.7
13.9
13.2
18.1
17.4
15.4
15.3
14.1
12.6
11.2
10.5
34.3
32.4
36.5
35.8
32.8
31.9
30.6
29.2
26.8
25.2
37.7
36.8
38.0
37.9
35.4
34.1
33.2
32.3
30.4
29.4
20.1
19.3
24.7
23.9
21.1
21.1
19.3
17.7
15.6
15.0
Pivmecillinam (J01CA08) 0-6
0.01
0.01
0.01
0.02
0.01
0.01
0.01
0.01
0.5
0.7
0.8
1.1
1.0
1.0
1.0
1.0
0.5
0.6
0.8
1.0
1.0
0.9
0.9
1.0
7-19
0.19
0.24
0.24
0.24
0.22
0.21
0.20
0.20
12.4
15.5
16.1
15.9
15.7
14.4
13.8
13.4
10.9
13.5
13.9
13.9
13.5
12.5
12.0
11.7
20-64
0.38
0.45
0.45
0.46
0.45
0.44
0.46
0.48
23.0
27.8
28.2
28.6
29.2
28.7
29.5
29.8
19.6 23.2
23.6
24.0
24.3
23.8
24.3
24.6
65-79
0.87
0.98
0.98
0.97
0.95
0.93
0.98
1.00
50.6
57.7
57.9
57.5
58.7
57.3
59.3
59.5
39.4
44.1
43.7
43.3
44.0
42.8
44.0
44.2
80-
1.84
1.94
1.92
1.90
1.79
1.75
1.83
1.92 109.3 116.6 115.8 115.0 112.6 109.3 112.3 114.7
81.9
85.5
83.9
83.1
81.4
78.4
80.5
82.1
All age groups
0.46
0.53
0.54
0.53
0.52
0.51
0.53
0.55
22.5
25.8
26.0
26.2
26.4
25.7
26.3
26.5
0-6
4.03
4.13
3.56
3.71
3.52
3.78
3.07
2.82 350.7 343.7 287.4 290.6 271.1 285.9 226.3 211.5 251.3 244.4 211.8 218.7 198.8 205.6 169.8 159.2
7-19
3.68
3.63
3.46
3.52
3.61
3.47
2.92
2.66 142.5 135.0 123.3 124.6 127.5 124.1 103.6
94.0 116.3 109.6 100.9 102.1 103.5
99.1
83.9
75.7
20-64
4.53
4.43
4.05
3.99
4.09
3.95
3.55
3.24 113.0 108.5
98.2
96.8
98.6
95.1
84.8
77.6
95.5
91.6
84.3
83.4
85.0
81.4
72.7
66.2
65-79
4.42
4.40
4.16
4.01
4.18
3.96
3.86
3.58 106.0 104.1
97.8
94.5
98.4
93.9
89.9
83.4
89.0
87.4
83.2
81.0
84.4
80.3
76.4
70.4
80-
3.36
3.50
3.38
3.29
3.33
3.34
3.24
3.07
81.7
79.5
80.4
81.0
78.3
73.9
72.3
72.7
69.9
68.3
69.5
69.6
67.4
63.3
All age groups
4.30
4.25
3.96
3.93
3.99
3.88
3.49
3.21 134.3 130.0 118.6 118.4 117.7 115.7 101.1
93.1 108.8 104.9
96.2
96.1
96.2
93.5
82.7
75.8
27.6
32.2
32.8
33.0
33.5
32.8
33.7
34.0
Beta-lactamase sensitive penicillins (J01CE)
84.2
85.7
Beta-lactamase resistant penicillins (J01CF) 0-6
0.33
0.33
0.31
0.30
0.28
0.29
0.26
0.26
32.9
32.8
30.8
29.4
28.0
29.0
26.1
26.2
25.9
25.6
24.3
23.4
22.0
22.9
20.4
20.6
7-19
0.69
0.80
0.79
0.77
0.76
0.77
0.78
0.77
31.9
31.9
31.2
31.0
30.0
28.5
27.8
27.4
26.2
26.0
25.4
25.5
24.6
23.1
22.6
22.2
20-64
1.04
1.22
1.20
1.18
1.19
1.27
1.31
1.30
34.9
34.8
34.0
34.2
33.9
33.0
32.2
32.1
27.6
27.4
26.9
27.4
27.0
26.3
25.6
25.5
65-79
2.24
2.63
2.55
2.52
2.51
2.67
2.77
2.74
61.4
62.5
60.8
60.0
58.5
58.1
57.1
56.2
40.4
40.9
39.9
40.3
39.5
38.6
38.1
37.3
80-
4.40
4.99
4.92
4.92
4.69
4.85
5.11
5.18 122.6 122.1 119.4 113.2 106.2 103.2 103.2 102.6
68.0
67.1
65.5
66.8
64.8
63.2
63.4
62.8
All age groups
1.25
1.46
1.45
1.43
1.42
1.51
1.56
1.56
38.5
30.9
30.8
30.2
30.6
29.9
29.2
28.5
28.2
13.5
36.2
31.9
24.0
17.9
12.3
11.1
8.8
8.3
42.2
42.3
41.7
41.3
40.3
39.5
38.7
Combinations of penicillins (J01CR) 0-6
0.75
0.67
0.52
0.39
0.28
0.26
0.21
0.21
52.7
46.4
33.7
25.3
17.8
16.7 13.9
7-19
0.21
0.20
0.18
0.17
0.16
0.14
0.14
0.14
6.4
6.0
5.4
4.9
4.7
4.0
3.9
4.0
4.9
4.5
4.1
3.8
3.6
3.0
2.8
2.7
20-64
0.21
0.22
0.21
0.22
0.22
0.22
0.22
0.24
4.5
4.7
4.4
4.7
4.7
4.7
4.7
5.0
4.0
4.1
3.8
4.0
4.0
3.9
3.9
4.0
65-79
0.23
0.27
0.29
0.31
0.32
0.34
0.34
0.37
4.8
5.5
5.7
6.1
6.3
6.7
6.8
7.5
3.9
4.3
4.6
4.8
5.0
5.1
5.2
5.6
80-
0.17
0.20
0.22
0.24
0.27
0.29
0.32
0.35
3.4
4.1
4.3
4.8
5.2
5.8
6.2
6.7
2.7
3.2
3.4
3.9
4.1
4.3
4.6
5.0
All age groups
0.26
0.26
0.24
0.24
0.24
0.23
0.23
0.25
8.5
8.3
7.2
6.7
6.1
6.0
5.8
6.1
6.5
6.3
5.5
5.2
4.7
4.6
4.4
4.5
Cephalosporins (J01DB-DE) 0-6
0.52
0.46
0.36
0.34
0.32
0.32
0.27
0.27
49.7
43.6
34.1
33.2
31.6
29.2
25.7
26.9
39.0
34.9
28.2
27.7
25.6
24.1
21.2
22.2
7-19
0.29
0.26
0.21
0.20
0.18
0.16
0.15
0.13
20.2
18.4
14.9
13.8
12.8
11.6
10.4
9.3
17.1
15.6
12.7
11.6
10.7
9.6
8.5
7.6
20-64
0.29
0.26
0.20
0.18
0.15
0.14
0.12
0.11
16.4
14.6
11.5
10.3
9.2
8.2
7.3
6.7
13.8
12.3
9.7
8.7
7.7
6.8
6.0
5.5
65-79
0.43
0.39
0.31
0.29
0.23
0.20
0.19
0.17
21.7
19.1
14.9
13.9
12.6
11.0
10.4
9.4
17.0
14.8
11.5
10.6
9.5
8.2
7.8
7.0
80-
0.65
0.54
0.41
0.38
0.34
0.32
0.31
0.29
35.4
29.4
22.7
21.6
19.9
18.5
17.6
17.0
27.5
23.0
17.9
16.6
15.5
14.2
13.4
13.1
All age groups
0.35
0.31
0.25
0.23
0.20
0.18
0.16
0.14
21.5
19.0
15.2
14.1
12.8
11.5
10.4
9.8
17.4
15.4
12.3
11.4
10.3
9.2
8.3
7.8
SWEDRES | SVARM 2014
DDD/1000 and day Age groups (years)
Prescriptions/1000 and year
User/1000 and year
2007 2008 2009 2010 2011 2012 2013 2014 2007 2008 2009 2010 2011 2012 2013 2014 2007 2008 2009 2010 2011 2012 2013 2014 Trimethoprim (J01EA)
0-6
0.12
0.10
0.09
0.09
0.08
0.08
0.07
0.07
15.4
14.0
12.6
12.2
11.3
11.0
10.0
9.2
10.8
10.1
9.7
9.5
8.8
8.4
7.6
6.9
7-19
0.18
0.15
0.11
0.10
0.08
0.06
0.05
0.04
10.9
8.9
7.0
5.9
4.8
3.9
3.3
2.8
9.4
7.7
6.0
5.1
4.1
3.3
2.7
2.2
20-64
0.31
0.26
0.20
0.17
0.15
0.13
0.11
0.10
15.6
12.7
9.4
7.8
6.5
5.4
4.5
3.9
13.0
10.5
7.7
6.4
5.2
4.3
3.5
3.0
65-79
0.90
0.76
0.61
0.57
0.50
0.43
0.39
0.34
42.0
34.7
27.5
24.3
20.9
17.7
15.5
13.5
30.9
25.1
19.6
17.3
14.6
12.3
10.7
9.2
80-
1.91
1.58
1.30
1.23
1.08
0.94
0.83
0.71 104.5
84.7
69.6
63.6
56.4
49.1
41.5
35.5
61.7
49.3
38.6
34.5
29.4
24.6
21.4
18.8
All age groups
0.43
0.36
0.29
0.26
0.23
0.20
0.17
0.15
18.8
14.9
13.1
11.2
9.7
8.3
7.2
17.0
13.9
10.7
9.3
7.9
6.7
5.7
4.9
22.8
Trimethoprim with sulphonamides (J01EE) 0-6
0.16
0.14
0.13
0.12
0.10
0.10
0.09
0.09
18.8
16.7
14.8
13.7
11.8
11.8
10.2
9.6
13.9
12.4
10.7
10.0
8.2
7.6
6.2
5.7
7-19
0.10
0.10
0.11
0.10
0.10
0.10
0.10
0.10
4.1
4.2
4.3
4.0
4.1
3.9
3.8
3.8
2.6
2.6
2.6
2.4
2.5
2.2
2.1
2.0
20-64
0.16
0.17
0.18
0.19
0.19
0.19
0.20
0.20
3.5
3.6
3.8
4.0
4.2
4.3
4.6
4.8
2.3
2.4
2.5
2.6
2.7
2.6
2.6
2.7
65-79
0.42
0.48
0.52
0.52
0.54
0.54
0.56
0.57
10.2
11.3
11.7
12.1
12.2
12.2
12.4
13.0
7.1
7.9
8.2
8.5
8.5
8.3
8.4
8.6
80-
0.39
0.43
0.43
0.46
0.46
0.47
0.51
0.51
12.2
13.1
12.5
13.1
12.5
12.6
13.0
13.2
9.1
10.0
9.7
10.1
9.8
9.5
9.7
9.9
All age groups
0.20
0.21
0.22
0.23
0.24
0.24
0.25
0.25
6.4
6.5
6.6
6.8
6.7
6.6
6.7
6.8
4.2
4.3
4.3
4.3
4.2
4.1
4.0
4.0
Macrolides (J01FA) 0-6
0.85
0.68
0.51
0.53
0.51
0.39
0.26
0.26
38.1
29.9
22.4
23.1
22.2
18.1
12.1
12.4
31.2
24.0
18.1
18.7
18.3
14.8
9.5
9.7
7-19
0.51
0.38
0.31
0.33
0.40
0.32
0.24
0.22
21.7
15.4
12.7
13.8
15.4
13.2
8.3
8.6
17.0
11.7
9.7
10.7
12.1
10.0
5.8
6.1
20-64
0.36
0.33
0.28
0.28
0.28
0.30
0.27
0.24
16.5
14.3
12.0
11.9
10.4
11.4
8.7
9.1
13.1 11.3
9.5
9.5
8.3
8.8
6.4
6.8
65-79
0.35
0.34
0.32
0.30
0.32
0.32
0.33
0.30
13.9
12.4
11.1
10.3
9.3
10.4
8.7
9.0
10.6
9.3
8.2
7.6
6.7
7.4
5.6
5.9
80-
0.24
0.23
0.23
0.21
0.20
0.19
0.20
0.19
8.7
8.4
7.4
6.9
6.0
6.4
5.7
5.8
6.8
6.4
5.5
5.3
4.4
4.8
4.0
4.0
All age groups
0.42
0.36
0.31
0.31
0.32
0.31
0.27
0.25
18.4
15.3
12.8
12.8
11.9
11.9
8.9
9.2
14.5
11.9
9.9
10.0
9.3
9.1
6.3
6.7
0-6
0.03
0.02
0.02
0.02
0.02
0.03
0.02
0.02
5.3
5.0
5.2
5.0
5.3
6.5
5.0
5.1
4.0
3.8
3.8
3.9
4.0
4.9
3.7
3.6
7-19
0.12
0.12
0.12
0.12
0.12
0.12
0.11
0.11
8.3
8.4
8.2
8.1
8.0
7.9
7.4
7.3
6.7
6.8
6.6
6.5
6.5
6.5
5.9
5.7
20-64
0.32
0.32
0.31
0.31
0.32
0.32
0.31
0.31
16.3
16.3
15.7
15.6
16.0
15.8
15.4
14.7
12.5
12.7
12.4
12.4
12.7
12.5
12.2
11.5
65-79
0.59
0.61
0.61
0.59
0.59
0.58
0.58
0.56
25.8
26.2
25.4
25.0
24.6
24.2
24.3
22.9
16.9
17.3
17.1
16.9
16.8
16.8
16.8
15.7
80-
0.74
0.76
0.72
0.73
0.71
0.70
0.71
0.73
32.8
33.2
31.0
31.7
30.8
30.2
29.9
29.9
18.7
19.3
18.8
19.2
19.0
18.7
18.9
18.9
All age groups
0.32
0.33
0.32
0.32
0.33
0.32
0.32
0.32
16.3
16.4
15.9
15.9
16.0
16.0
15.6
14.9
11.8
12.0
11.7
11.7
11.9
11.9
11.6
11.0
0.4
Lincosamides (J01FF)
Fluoroquinolones (J01MA) 0-6
0.01
0.01
0.01
0.01
0.01
0.01
0.02
0.02
0.8
0.7
0.7
0.8
0.7
0.7
0.9
0.8
0.4
0.4
0.4
0.5
0.4
0.5
0.5
7-19
0.13
0.12
0.12
0.12
0.12
0.11
0.11
0.10
5.5
4.8
4.3
4.3
4.3
4.0
3.6
3.4
4.4
3.8
3.5
3.5
3.4
3.2
2.9
2.7
20-64
0.86
0.78
0.72
0.68
0.68
0.65
0.62
0.59
31.4
27.0
23.8
22.9
21.9
20.8
19.7
18.9
22.6
19.5
17.3
16.7
15.9
15.1
14.4
13.8
65-79
2.10
1.90
1.84
1.79
1.77
1.73
1.64
1.61
81.4
70.8
65.6
63.8
61.1
58.8
55.7
54.8
55.1
48.3
44.9
43.9
41.8
40.4
38.6
37.6
80-
2.74
2.41
2.25
2.26
2.18
2.08
2.00
1.95 119.7
98.5
88.2
87.3
82.0
77.6
73.7
72.5
81.6
68.4
61.4
60.9
57.8
54.9
52.6
51.4
All age groups
0.93
0.84
0.80
0.78
0.77
0.75
0.71
0.69
30.6
27.8
27.1
26.1
25.0
23.8
23.3
25.0
21.7
19.6
19.2
18.4
17.7
16.9
16.4
7.2
4.3
4.3
5.0
5.1
5.1
5.0
5.1
5.2
35.7
Nitrofurantoin (J01XE) 0-6
0.07
0.06
0.06
0.06
0.06
0.05
0.05
0.06
6.3
7-19
0.14
0.13
0.15
0.14
0.14
0.13
0.13
0.13
6.7
20-64
0.25
0.24
0.27
0.27
0.28
0.29
0.30
0.31
11.3
65-79
0.53
0.55
0.62
0.61
0.64
0.67
0.72
0.74
22.6
80-
0.97
0.95
1.05
1.06
1.12
1.15
1.23
1.30
46.7
All age groups
0.30
0.29
0.32
0.32
0.34
0.35
0.37
0.38
13.5
6.2
6.9
7.2
7.3
7.0
7.1
6.6
9.2
10.6
10.8
10.4
10.1
9.8
5.7
5.7
7.9
9.0
9.2
8.9
8.6
8.3
11.1
15.3
17.8
19.1
19.8
20.5
21.1
9.3
9.1
12.5
14.6
15.6
16.1
16.6
17.0
24.2
32.6
37.3
39.9
41.5
44.0
44.9
16.9
18.1
24.0
27.5
29.3
30.3
31.9
32.5
47.7
61.7
70.6
76.0
77.4
80.6
84.0
30.4
31.3
40.3
45.6
47.8
49.0
51.6
53.8
13.6
18.5
21.3
22.8
23.5
24.5
25.1
10.4
10.5
14.1
16.3
17.3
17.8
18.4
18.9
All agents (J01 excl. Methenamine) 0-6
8.61
8.32
7.11
7.21
6.55
6.66
5.43
5.15 666.8 630.8 522.4 515.0 467.6 471.9 382.4 367.2 358.6 342.4 299.5 300.7 273.3 274.4 232.0 222.7
7-19
9.95
9.83
9.52
9.65
9.83
9.27
8.33
7.75 319.8 301.4 280.8 282.5 286.1 268.0 232.7 217.8 206.5 194.6 182.5 183.8 185.5 173.2 152.1 141.8
20-64
13.34 13.09 12.14 12.03 12.25 11.98 11.19 10.62 380.4 361.7 331.8 329.9 331.7 320.0 294.4 280.8 234.9 224.7 209.1 207.8 208.9 200.7 184.9 175.8
65-79
19.13 19.16 18.23 17.78 18.00 17.76 17.28 16.55 587.3 566.6 535.0 525.3 524.7 510.7 489.2 468.7 306.9 297.5 282.9 278.6 278.9 270.6 258.1 246.5
80-
22.25 22.24 21.13 20.85 20.38 20.34 20.22 19.95 807.9 765.1 723.5 710.9 690.7 673.0 654.2 640.3 373.0 357.7 340.2 336.1 330.9 323.2 314.7 307.8
All age groups 13.70 13.53 12.76 12.68 12.76 12.51 11.74 11.20 443.8 423.1 391.9 390.3 385.3 373.9 342.7 328.0 255.9 245.1 228.3 227.5 226.3 218.7 201.0 191.7
21
SWEDRES | SVARM 2014
Narrow spectrum penicillin, penicillin V, is the recommended first line antibiotic for treatment of community acquired RTI in Sweden (Medical Products Agency & Strama, 2008) and is the most frequently prescribed antibiotic in outpatient care, Figure 1.8. The sales of penicillin V decreased in all age groups during 2014 compared to 2013, but to a variable extent, Table 1.2. Doxycycline is the second most frequently prescribed antibiotic agent in outpatient care. 98% of all doxycycline packages sold on prescriptions are containing less than 50 tablets, which indicates that the substance is mainly used to treat RTI, Figure 1.8. The sales pattern differ between age groups. In the age group 65 years and older, broader antibiotic substances doxycycline and amoxicillin are used to a greater extent, Figure 1.9. Even though the total sales of antibiotics commonly used to treat RTI decreased during 2014 the sales of macrolides and amoxicillin with clavulanic acid increased by 4 and 5% respectively, Figure 1.8. During spring 2013, the pharmacy ran out of macrolides in Sweden which may affect the statistics and partly explain the increase seen during 2014. The increased sales of amoxicillin with clavulanic acid might be a consequence of an increased number of urinary tract infections caused by ESBL producing bacteria, where amoxicillin with clavulanic acid could possibly be an oral treatment alternative (Public Health Agency of Sweden, 2014). In addition, amoxicillin with clavulanic acid has since 2013 been part of initial sensitivity testing against Enterobacteriaceae for patient with uncomplicated UTI. This might have affected the prescription rate of amoxicillin with clavulanic for this indication (RAF, 2013). However, when analyzing the sales of antibiotics commonly used to treat RTI during 2014 compared with 2013 a noteworthy reduction exists throughout the year. The greatest decrease during 2014 was seen for doxycycline (packages smaller than 50 tablets) (10%) and penicillin V (8%). The
decrease in sales of doxycycline seen during the last two years may indicate an improved compliance to national treatment recommendations (Medical Products Agency and Strama, 2008) where it is stated that acute bronchitis (including Mycoplasma pneuomoniae) should generally not be treated with antibiotics. As cited in previous Swedres-Svarm, a new national recommendation for treatment of pharyngotonsillitis was published in 2012 (Medical Products Agency & Swedish Institute for Communicable Disease Control, 2012). Successful communication about treatment recommendations may be one contributed explanation for the decreased sales of antibiotics commonly used to treat RTI. Furthermore, the ESAC-net quality indicator (ECDC; 2014) for seasonal variation shows less seasonal variation in the sales of antibiotics over the years in Sweden. This indicates a more rational antibiotic use and less misuse of antibiotics for cold or flu, Figure 1.10.
Figure 1.8. Sales of antibiotics commonly used to treat respiratory tract infections in outpatient care (sales on prescriptions), 2000-2014, prescriptions/1 000 inhabitants and year, both sexes, all ages.
Figure 1.10. ESAC quality indicator on seasonal variation of the total antibiotic consumption (J01 excl. methenamine) of a 12-month period starting in July and ending the following June, expressed as percentage. Total sales of antibiotic on prescription in Sweden 2000-2014.
Figure 1.9. Sales of antibiotics commonly used to treat respiratory tract infections in outpatient care (sales on prescriptions), 2014, prescriptions/1 000 inhabitants and year, both sexes, different age groups.
Prescriptions/1000 inhabitants
250 200 150 100 50 0 0-6 years
*Excludes packages containing more than 50 tablets
2013/2014
2012/2013
2011/2012
2010/2011
2009/2010
2008/2009
2007/2008
0
2006/2007
2014
2013
2012
2011
2010
2009
2008
2007
2006
Cephalosporins (J01DB-DE) Macrolides (J01FA) Amoxicillin with clavulanic acid (J01CR02)
5
2004/2005
Penicillin V (J01CE02) Doxycycline (J01AA02)* Amoxicillin (J01CA04)
2005
2004
2002
2003
0
2001
20
10
2005/2006
40
2002/2003
60
15
2003/2004
80
20
2001/2002
100
65 years and older
25
2000/2001
120
20-64 years
Amoxicillin (J01CA04) Amoxicillin with clavulanic acid (J01CR02) Cephalosporins (J01DB-DE)
*Excludes packages containing more than 50 tablets
Percent (DDD per 1000 inhabitants and day (winter quarters)/DDD per 1000 inhabitants and day (summer quarters)-1] x100)
140
7-19 years
Doxycycline (J01AA02)* Penicillin V (J01CE02) Macrolides (J01FA)
160
2000
Prescriptions/1000 inhabitants and year
22
SWEDRES | SVARM 2014
Antibiotics commonly used to treat urinary tract infections in women
Antibiotics commonly used to treat urinary tract infections in men
National treatment recommendations for lower urinary tract infections in women over 18 years (Medical Products Agency & Strama, 2007), recommends pivmecillinam and nitrofurantoin before trimethoprim, and prescribers are also encouraged to minimize the use of fluoroquinolones because of the resistance situation. In 2014, the total sales of antibiotics commonly used to treat UTI in women aged 18-79 years slightly decreased (1%) compared with 2013. However, the same positive trend as previously with increased use of the first-line drugs pivmecillinam and nitrofurantoin and reduced sales of trimethoprim (13%) and fluoroquinolones (2%) was also seen, Figure 1.11. The total sales of these antibiotics have decreased slowly over the years; by 2% since 2000, as measured by prescriptions per 1 000 women and year. However, if measured by DDD per 1 000 women and day, the sales has decreased by 13% since 2000. This suggest shorter treatment duration for this condition with time, which is also according to recommendations. Antibiotics commonly used to treat UTI is mostly prescribed to the age group 65 years and older, Figure 1.7. In this age group the total sales has decreased by 20% since 2000, as measured by prescriptions per 1 000 women and year. As mentioned in the chapter “Guidance for readers”, some of the antibiotic use among elderly people is not included in the statistics and a possible under-estimation in the age group 65 years and older cannot be ruled out. Nevertheless, the great decrease in the age group 65 years and older indicates increased compliance to recommendations. Many elderly have asymptomatic bacteria in urine (ABU) and should not normally be treated with antibiotics (Medical Products Agency & STRAMA, 2007). Information and education at local and national level regarding treatment recommendation and ABU might be one explanation for the great decrease in sales over time in this age group. The same trend is seen in men, see below.
The total sales of antibiotics commonly used to treat UTI in men 65 years and older has decreased by 27% since 2000. In 2014, however, the sales slightly increased (1%). Because of increasing resistance in gram-negative bacteria, the use of fluoroquinolones has been questioned and nitrofurantoin and pivmecillinam may now be considered as first line antibiotics for treatment of symptomatic UTI without fever in men (Public Health Agency of Sweden, 2013). The sales of fluoroquinolones to men aged 65 years and older has decreased significantly since 2000 (37%), as measured by prescriptions per 1 000 men and year. The decrease continued in 2014 by 2% compared with 2013. During the last years, sales of pivmecillinam and nitrofurantoin have increased. In 2014, the sales of these two antibiotics increased by 20% and 12% respectively, as measured by prescriptions per 1 000 men and year, compared with 2013, Figure 1.12.
Figure 1.11. Sales of antibiotics commonly used to treat lower urinary tract infections in women (sales on prescriptions), 18-79 years, 20002014, prescriptions/1 000 women and year.
Antibiotic consumption in children The total sales of antibiotics to children aged 0-6 years has decreased by 51% since 2000 (from 746 to 367 prescriptions per 1 000 children and year). Between 2013 to 2014, the sales decreased by 4%. A decrease was seen in 17 out of 21 counties. There are still great national variations in antibiotic sales to children 0-6 years, from 432 prescriptions per 1 000 children and year in Stockholm County to 200 in Jämtland County, Figure 1.13. The great variation between the counties may suggest antibiotic overuse in some counties. Even counties with the lowest antibiotic sales continued to decrease significantly during 2014, which also suggests antibiotic overuse in other counties. The reduction in sales during 2014 includes the majority of the available antibiotic agents, Table 1.2. Measured by prescriptions, the greatest decrease 2014 was seen in the sales of penicillin V (15 prescriptions/1 000 children and year)
Figure 1.12. Sales of antibiotics commonly used to treat UTI in men 65 years and older 2000-2014, measured as prescriptions/1 000 men and year. 140 Prescriptions/1000 men and year
70 60 50 40 30 20 10 0
120 100 80 60 40 20
2014
2013
2012
2011
2009
2010
2008
2007
2006
2005
2003
2004
2001
2002
2000
2013
2014
2011
2012
2010
2008
2009
2007
2006
2005
2004
2002
2003
2001
0 2000
Prescriptions/1000 women and year
80
Pivmecillinam (J01CA08)
Nitrofurantoin (J01XE)
Fluoroquinolones (J01MA02+06)
Pivmecillinam (J01CA08)
Fluoroquinolones (J01MA02+06)
Trimethoprim (J01EA)
Nitrofurantoin (J01XE01) Trimethoprim (J01EA01)
Trimethoprim with sulphonamides (J01EE)
23
SWEDRES | SVARM 2014
Medical Products Agency in 2010 (Medical Products Agency & Strama, 2010). The new recommendations have been attracting attention from professionals and the public which may have influenced the antibiotic use in young children. In Sweden, the proportion of children (0-6 years) treated with at least one course of antibiotics was 22%, which is less than in 2013, Table 1.2. The proportion decreased in 18 out of 21 counties during 2014 and it ranges within the country, from 257 users per 1 000 children in Stockholm County to 130 users per 1 000 children in Jämtland County, Figure 1.15.
followed by trimethoprim (1 prescriptions/1 000 children and year), Figure 1.14. Different kinds of penicillins are the most commonly prescribed antibiotics in this age group and penicillin V (J01CE02), amoxicillin (J01CA04) and flucloxacillin (J01CF05) represent 77% of the total sales in 2014, Table 1.2 and Figure 1.14. The great decrease in antibiotic sales seen over time in children can be explained by a more appropriate antibiotic use in Sweden. New recommendations for treatment of acute otitis media were launched by Strama and the Swedish
Figure 1.13. Sales of antibiotics (J01 excl. methenamine) on prescriptions to children 0-6 years, per county and in Sweden, prescriptions/1 000 children and year. The data are sorted according to the use in 2014. A decrease is seen in 17 out of 21 counties during 2014.
Prescriptions/1000 children and year
900 800 700 600 500 400 300 200 100
2007
2009
2010
2011
2012
2013
tte
tla m Jä
bo er
Vä
st
nd
n
n te
na N
or
D
rb
al
ot
ar
an
d
rg
rrl no
er st
Vä
Ö 2008
bo
ar
le
lm G
äv
nd
la
la ot G
rm Vä
Ka
nd
g in
g Jö
nk
öp
er
nd
ob
la
Kr
on
al
tla gö
st
er
H
br
nd
o
ge in
re Ö
nd la
ek Bl
an m st
G ra
Vä
st
Vä
öt
al
an
la
an
d
nd
en rm Sö
de
sa pp
ed
la
e ån U
Sk
Sw
St
oc
kh
ol
m
0
2014
Figure 1.14. Sales of antibiotics in outpatient care to children 0-6 years, 2000-2014, prescriptions/1 000 inhabitants and year, both sexes. The data are sorted according to ATC codes.
Prescriptions/1000 children and year
450 400 350 300 250 200 150 100 50
2000
2005
2007
th O
2008
2009
2010
2011
2012
2013
er ( J0 J01 1F AA F ,J an 0 d 1C J0 A 1M 08 A) ,
n oi nt ur a of itr -N E 1X
J0
J0 Ce 1DB ph al J0 os 1D po E rin s J0 1E A -T rim et ho pr im J0 1E w E ith su Trim lp e ho th na op m rim id es J0 1F A -M ac ro lid es
0
ex J01 te CA nd ed P sp enic ec ill tru ins m w ex ith J0 cl 1C . E se ns Be iti ta ve lac pe tam ni a ci se llin J0 s 1C F re - B si st eta an la t p ct en am ic as illi e ns J0 1C R -C o of mb pe ina ni tio ci n llin s s
24
2014
SWEDRES | SVARM 2014
Figure 1.15. Proportion of children 0-6 years treated with at least one course of antibiotics (J01 excl. methenamine) in 2012-2014 (user/1 000 children and year).
Figure 1.16. Proportion of people treated with at least one course of antibiotics (J01 excl. methenamine) in 2012-2014 (user/1 000 inhabitants and year).
2012
2013
2014
2012
2013
2014
Users/1000 inhabitants
Users/1000 inhabitants
Users/1000 inhabitants
Users/1000 inhabitants
Users/1000 inhabitants
Users/1000 inhabitants
<210 210−229 230−249 250−289 290−309 310−329 330−369
<210 210−229 230−249 250−289 290−309 310−329 330−369
<210 210−229 230−249 250−289 290−309 310−329 330−369
<210 210−229 230−249 250−289 290−309 310−329 330−369
County data
<210 210−229 230−249 250−289 290−309 310−329 330−369
<210 210−229 230−249 250−289 290−309 310−329 330−369
during the latest years might be the patient safety initiative, that started in 2011 and continued until the end of 2014. This is a governmental performance-based initiative partly focusing on optimizing the antibiotic use through financial incentives (Public Health Agency of Sweden, 2014). Reed more about the agreement and evaluation on antibiotic use in relation to the initiative in the chapter “National campaign for improved patient safety”. There are still great regional differences between different parts of Sweden and prescriptions per 1 000 inhabitants range from 359 in Stockholm County to 260 in Västerbotten County, Figure 1.17. The great variation between counties is probably not explained by differences in morbidity (Hedin K, Andre M, et al. 2006), but more likely explained by overuse of antibiotics. Factors influencing antibiotic prescription at healthcare centers has been investigated in a recently published study, see results from the study in a report on the webpage of the
In 2014, 19% of the Swedish population was treated with at least one course of antibiotics, which is marginally less than in 2013 where 20% was treated, Table 1.2. However, the proportion of people treated with antibiotics varies within Sweden, from 21% in Stockholm County to 15% in Västerbotten County. The antibiotic use is greatest in big cities and their surroundings. In total, the proportion of patients treated decreased in all counties in 2014, Figure 1.16. In 2014, the average sales of antibiotics in outpatient care measured as prescriptions per 1 000 inhabitants in Sweden was 328. To reach the Swedish long term target of 250 prescriptions per 1 000 inhabitants and year the antibiotic use in Sweden still must be reduced by 24%, Figure 1.17. In 2014, a reduced number of prescriptions per 1 000 inhabitants was seen in all 21 counties, Figure 1.17. One reason for the great decrease in antibiotic sales in all counties in Sweden
Figure 1.17. Sales of antibiotics in outpatient care 2012-2014, prescriptions/1 000 inhabitants and year. The red line indicates the Swedish long term target of 250 prescriptions/1 000 inhabitants and year. The data are sorted according to the sales in 2014.
400 350 300 250 200 150 100 50
2012
2013
2014
n
Vä st e
rb
ot
te
nd
rg le
tla
Jä
äv
m
bo
na ar al G
D
la nd Jö nk ö p Vä in st g er no rrl an d N or rb ot te n
o br re
Vä rm
Ö
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st
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an Vä la st nd ra G öt al an d Bl ek in ge H al la Sö nd de rm an la nd Ö st er gö tla nd Ka lm ar Kr on ob er g
en
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ed
sa pp
Sw
G
la
e ån U
Sk
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m
0
St
Prescriptions/1000 inhabitants and year
450
25
SWEDRES | SVARM 2014
Agency of Sweden is regularly analyzing the incidence of known complications. Despite the great decrease in antibiotic sales to children over the last years, incidence of mastoiditis have not increased. Read more about this in SwedresSvarm 2013 (Swedres-Svarm 2013). As mentioned in earlier editions of Swedres-Svarm, Strama has proposed two qualitative targets for antibiotic prescribing in outpatient care: 1. At least 80% of antibiotics commonly used to treat respiratory tract infections in children aged 0-6 years should be penicillin V (J01CE02). The numerator is penicillin V (J01CE02) and the denominator is amoxicillin (J01CA04), penicillin V (J01CE02), amoxicillin-clavulanate (J01CR02), cephalosporins (J01DB-DE) and macrolides (J01FA).
Public Health Agency of Sweden (Public Helath Agency of Sweden, 2014). Factors that seems to positively affect antibiotic prescribing habits are for example; “time and forum for discussion about management and treatment of respiratory tract infections within and between professional groups”, “leadership and support to local opinion leaders” and “interprofessional collaboration”. Earlier studies have shown overuse of antibiotics in RTI (Mölstad S, Andre M, et al. 2009, Neumark T et al. 2009). Notably, the greatest differences in the sales of antibiotics between counties relate to treatment of RTI, Figure 1.18. This supports the hypothesis of overuse. When promoting appropriate use of antibiotics, it is of great importance to study and analyze the incidence of morbidity and complications, to ensure that these do not increase as a consequence of a more restricted use. The Public Health
Figure 1.18. Sales of antibiotics commonly used to treat RTI (J01AA02*, J01CE02, J01CA04, J01CR02, J01DB-DE and J01FA), UTI (J01CA08, J01EA01, J01MA02, J01MA06 and J01XE01), SSTI (J01FF01 and J01CF05) and other antibiotics in outpatient care 2014, per county, prescriptions/1 000 inhabitants. The data are sorted according to the county with the highest sales of antibiotics commonly used to treat RTI. 250 Prescriptions/1000 inhabitants
200
150
100
50
Antibiotics commonly used to treat SSTI
Antibiotics commonly used to treat UTI
Antibiotics commonly used to treat RTI
Other antibiotics
n bo er
st Vä
Jä
m
tla
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G
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ot
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nd
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la
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rm Vä
D
g
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Jö
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re
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la
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gö er
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Sö
Ö
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H
nd
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de
Bl
la
an
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Vä
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d
en
la sa
ed Sw
pp U
oc
kh
Sk
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e
0
St
26
*Excluding packages containing more than 50 tablets.
Figure 1.19. Proportion penicillin V of antibiotics commonly used to treat respiratory tract infections in children 0-6 years, per county, 2013-2014. The red line indicates Strama´s goal at minimum 80% penicillin V. Värmland Västmanland Jönköping Blekinge Dalarna Kalmar Västernorrland Västerbotten Örebro Västra Götaland Gävleborg Östergötland Skåne Jämtland Norrbotten Sweden Halland Södermanland Gotland Uppsala Stockholm Kronoberg 0%
Figure 1.20. Proportion of fluoroquinolones of antibiotics commonly used to treat urinary tract infections in women 18-79 years, per county, 2013-2014. The red line indicates Strama´s goal of maximum 10% fluoroquinolones. Östergötland Kalmar Västra Götaland Värmland Stockholm Dalarna Jönköping Jämtland Uppsala Gotland Sweden Västmanland Skåne Norrbotten Blekinge Gävleborg Södermanland Kronoberg Örebro Västerbotten Halland Västernorrland
10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 2014
2013
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 2014
2013
SWEDRES | SVARM 2014
2014 was seen for amoxicillin (13%) and clindamycin (14%), measured as prescriptions per 1 000 inhabitants and year. Amoxicillin has decreased by 30% between 2012 and 2014, this might be cause of the new stricter treatment recommendations for the use of prophylaxis which was implemented in 2012. A big increase was seen for clindamycin between 2001 and 2011. Since 2012, the trend has reversed and the prescribing of clindamycin decreased each year hereafter. Dentists account for approximately 7% of all antibiotics prescribed in outpatient care in Sweden. The proportion varies between 4% in some counties to 7% in some counties. The total sales of antibiotics (J01 and metronidazole), measured as prescriptions per 1 000 inhabitants and year, decreased in 18 out of 21 counties in 2014 compared with 2013. Like in outpatient care, there are big differences between the counties. Dentists in Stockholm County prescribe the most (29 prescriptions/1 000 inhabitants) and Västerbotten County the least (14 prescriptions/ 1 000 inhabitants for 2014), see Figure 1.22.
In 2014 the proportion of penicillin V was 69% on a national level, which is marginally less than in 2013. Värmland County had the greatest proportion, 80%, and Kronoberg County the lowest, 65%, Figure 1.19. In total, 20 out of 21 counties decreased this proportion in 2014 compared to 2013. The great decrease in use of penicillin V to children during the latest years, from 351 prescriptions/1 000 inhabitants and year in 2007 to 212 in 2014, needs to be considered when analyzing this indicator. 2. The proportion of fluoroquinolones should not exceed 10% of antibiotics commonly prescribed to treat urinary tract infections in women 18-79 years. The numerator is ciprofloxacin (J01MA02) and norfloxacin (J01MA06) and the denominator is pivmecillinam (J01CA08), trimethoprim (J01EA01), ciprofloxacin (J01MA02), norfloxacin (J01MA06) and nitrofurantoin (J01XE01). In Sweden the average proportion was 13% in 2014. Väster norrland had the highest proportion (16%), Figure 1.20. When analyzing sales data excluding prescriptions from hospitals, the proportion of penicillin V to children was 75% in 2014 at a national level and the proportion of fluoroquinolones to women 18-79 years was 8%.
Figure 1.21. Sales of antibiotics prescribed by dentists in outpatient care, 2009-2014. Prescriptions/1000 inhabitants and year
35
Antibiotics in dentistry The sales of antibiotic prescribed by dentists decreased by 9% in 2014 compared with 2013, from 26.0 to 23.6 prescriptions per 1 000 inhabitants and year for J01 and metronidazole (P01AB01), see Figure 1.21. Penicillin V (J01CE02) is the most commonly prescribed antibiotic followed by amoxicillin (J01CA) and clindamycin (J01FFA01). These antibiotic substances represent 78%, 10% and 9% respectively of all antibiotics prescribed by dentists. However, the greatest decrease in
30 25 20 15 10 5 0
2009
2010
Penicillin V (J01CE02) Metronidazol (P01AB01)
2011
2012
Amoxicillin (J01CA04) Other (in the group J01)
2013
2014
Clindamycin (J01FF01) Erythromycin (J01FA01)
Figure 1.22. Sales of antibiotics prescribed by dentists in outpatient care per county, 2009-2014, Antibiotics for systemic use (J01) and metronidazol (P01AB01).
35 30 25 20 15 10 5
2010
2011
Kr
2012
2013
2014
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Vä st e
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ot
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Vä 2009
G
la al H
rn D
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Ka
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tla m
Bl
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Ö
st
er
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Vä
an
la
la
nd
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Sk å
Sö de r
oc
kh
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m
0
St
Perscriptions/ 1000 inhabitants and year
40
27
28
SWEDRES | SVARM 2014
In focus
National campaign for improved patient safety The Government and the Swedish Association of Local Authorities and Regions (SKL) agreed for the years 2011-2014 on a performance-based reimbursement to encourage, strengthen and intensify the work on patient safety efforts in the county councils. During these years just over SEK 2.2 billion was allocated to county councils as a stimulus, provided that they met certain basic requirements and implemented measures to increase patient safety in healthcare. The initiative identified antibiotic resistance and the rational use of antibiotics as central patient safety areas and a total of SEK 400 million was invested in this area. The Public Health Agency had a remit from the Government to annually evaluate the progress of the county councils to reach the goals of the antibiotics indicators. Performance indicators
One of the basic requirements to be eligible for the performance reimbursement, was the establishment of a local Strama group (strategic programme against antibiotic resistance) in each county with a clear mission and adequate financing. All the county councils met this requirement by 2011. Increased compliance to national treatment recommendations for common infections in outpatient care, was another key performance indicator. Furthermore a decrease in antibiotic sales towards the national target of 250 prescriptions per 1 000 inhabitants and year was rewarded each year. The national quantitative target for antibiotic prescriptions was launched by Strama in 2009, in conjunction with the European Antibiotic Awareness Day. The target was set with the knowledge that a large proportion of antibiotic use is unnecessary and was calculated based on an analysis of recorded visits for respiratory tract infections in primary care in Kalmar (Neumark T et al. 2009, Neumark T et al 2010). The target of 250 prescriptions per 1 000 inhabitants was at the launch a challenging goal given that the national average then was 382 prescriptions per 1 000 inhabitants. During the last two years of the campaign the county councils were also required to show that at least 50 percent of the county health centers had provided the general practitioners with their personal antibiotic prescribing data. Furthermore to accomplish set targets, the prescribing of the practitioners at each health care center should in a structured manner be compared to other health centers in the county and be discussed in relation to treatment recommendations. During the last year of the patient safety initiative, in 2014, the county councils also had to assess the effects of giving feed-back on the personal prescribing patterns.
Changes in antibiotic sales 2011-2014 Significant reductions in antibiotic sales was achieved during the campaign period where it decreased among men and women and in all age groups in all counties. In Sweden in total the number of prescriptions decreased with 15%, from 381 to 325 prescriptions/1 000 inhabitants and year. The decrease in each county ranged from 8% to 20%, see Table A. The results from the last measurement period showed that Västerbotten County was close to reaching the goal of 250 prescriptions per 1 000 inhabitants. The reduction indicates that there was a significant over-prescription of antibiotics when the campaign began in 2010, and that it is realistic and necessary to continue to work towards the 250 prescriptions-target. It´s of major importance that the decrease is established through increased compliance to national treatment recommendations. The 250 prescriptions- target must therefore be complemented by quality and safety indicators to assure development towards not only lower, but also a more appropriate prescription as well as to avoid under-prescription. Sales statistics at the national level shows that the prescription of the 15 most commonly prescribed substances (which accounted for 98 percent of all antibiotic sales) has decreased except for pivmecillinam, nitrofurantoin and azithromycin. The first two are the recommended first-line treatment options of lower urinary tract infections in women, which suggests an increased adherence to treatment recommendation for sporadic lower urinary tract infection in women. During spring 2013, the pharmacies ran out of erythromycin (J01FA01) in Sweden and the increased sales of azithromycin can probable be explained by a shift from erythromycin to azithromycin during that period. The largest reductions was seen in antibiotics commonly used against respiratory tract infections, like penicillin V, doxycycline and amoxicillin. This suggests that adherence to guidelines for otitis media, acute bronchitis and pharyngotonsillitis improved or that less antibiotics was prescribed for viral respiratory tract infections, or a combination thereof, see Table B.
Discussion There are several possible explanations for the decrease seen in the sales of antibiotics and the patient safety initiative is very likely to have contributed substantially. The campaign has raised increased awareness and highlighted the priority given at national level to work within the area of antibiotic resistance. This has led to reinforcement and consolidation of the existing structure of local Strama groups with close links to the national agencies in Sweden during the campaign period.
SWEDRES | SVARM 2014
29
Period 1
Period 4
1 Oct 2010 - 30 Sep 2011 1 Oct 2013 - 30 Sep 2014 Prescriptions/1000 inhabitants Prescriptions/1000 inhabitants
Decrease
Decrease
Prescriptions
Per cent
Stockholm
413
356
-57
-14%
Skåne
411
351
-60
-15%
Uppsala
374
336
-38
-10%
Gotland
380
327
-53
-14%
Sweden
381
325
-56
-15%
Västra Götaland
399
320
-79
-20%
Halland
381
320
-61
-16%
Blekinge
388
316
-72
-19%
Västmanland
366
316
-50
-14%
Södermanland
345
314
-31
-9%
Östergötland
352
314
-38
-11%
Kalmar
359
312
-47
-13%
Kronoberg
370
305
-65
-18%
Örebro
336
302
-34
-10%
Västernorrland
329
299
-30
-9%
Värmland
346
298
-48
-14%
Norrbotten
349
298
-51
-15%
Jönköping
355
296
-59
-17%
Dalarna
313
288
-25
-8%
Gävleborg
337
286
-51
-15%
Jämtland
307
272
-35
-11%
Västerbotten
310
261
-49
-16%
The campaign has intensified specific activities related to the performance based indicators in the county councils during the campaign period which is one possible explanation for the decrease in antibiotic sales. Many local Strama groups have for example completed systematic work directed towards prescribers with information campaigns to the general public and activities in relation to media. A coinciding change in the infection panorama with a reduced need for treatment may be an alternative explanation for the reduced sales of antibiotics. Another possibility could be that practitioners in general prescribe antibiotics more appropriately today. Sales data have declined in the other Nordic countries during the same period which suggests additional factors contributing to the decrease in sales. Even so, Sweden with its structure of local Strama groups systematically working with improvement of appropriate prescribing and implemen-
tation of treatment recommendations e.g. through personal feed-back is probably one important explanation to our lower prescription as compared to the other Nordic countries (Figure A). In the impact assessment the Strama group´s unanimous interpretation was that some of the key success factors are that physicians have access to their personal antibiotic prescribing data and discuss their prescription patterns within the entire health unit staff to develop a common practice around the management of the patients. An additional success factor is considered to be the local benchmarking against other neighboring health units. It is of great importance that the Swedish Strama model for implementing national treatment recommendations and improving antibiotic prescribing can further develop and be established as an integrated part of the local and regional health care organization. Studies have shown large differences in antibiotic prescribing between
In focus
Table A. The sales of antibiotics in all Swedish counties, comparing the Patient safety initiative’s first measurement period (1 October 201030 Sep 2011) with the last measurement period (1 October 2013-30 September 2014).
30
SWEDRES | SVARM 2014
health care units in the same area. High priority of quality improvement work at health care units has been identified as a possible factor for such variation. Strama groups are working effectively for quality improvement
and appropriate antibiotic use, nevertheless it must be emphasized that it is the County Council’s overall strategic responsibility to ensure that quality improvement and assurance is secured in all health units.
Penicillin V (J01CE02)
Period 1
Period 4
1 Oct 2010 - 30 Sep 2011
1 Oct 2013 - 30 Sep 2014
Diff
Diff%
116.7
92.1
-24.7
-21%
Flucloxacillin (J01CF05)
40.3
38.4
-1.8
-5%
Pivmecillinam (J01CA08)
33.1
33.7
0.6
2%
Doxycycline (J01AA02)
39.6
28.6
-11.0
-28%
Nitrofurantoin (J01XE01)
22.5
24.8
2.3
10%
Ciprofloxacin (J01MA02)
24.0
22.3
-1.7
-7%
Amoxicillin (J01CA04)
24.4
18.3
-6.2
-25%
Clindamycin (J01FF01)
15.9
14.9
-0.9
-6%
Lymecycline (J01AA04)
10.2
10.0
-0.2
-1%
Cefadroxil (J01DB05)
11.0
8.2
-2.8
-25%
Trimethoprim (J01EA01)
11.6
7.4
-4.2
-36%
Sulfamethoxazole and trimethoprim (J01EE01)
6.2
6.1
-0.1
-2%
Amoxicillin and enzyme inhibitor (J01CR02)
6.1
5.8
-0.3
-5%
Erythromycin (J01FA01)
8.4
5.3
-3.1
-37%
Azithromycin (J01FA10)
2.1
2.7
0.5
24%
Figure A. Sales statistics of antibiotic prescriptions during the patient Safety Initiatives first comparative period (1 Oct 2009-30 Sep 2010) and the four annual measurement periods October 2010 to September 2014 in the Nordic countries Sweden, Norway, Finland and Denmark. 700
600
500 Prescriptions/1000 inhabitants
In focus
Table B. Sales statistics at the national level of the 15 most commonly prescribed preparations (which accounted for 98 percent of all antibiotic prescriptions). Comparing the Patient safety initiative’s first measurement period (1 October 2010-30 Sep 2011) with the last measurement period (1 October 2013-30 September 2014).
400
1 Oct 2009-30 Sep 2010 1 Oct 2010-30 Sep 2011 1 Oct 2011-30 Sep 2012 1 Oct 2012-30 Sep 2013
300
1 Oct 2013-30 Sep 2014
200
100
0
Sweden
Norway
Finland
Danmark
SWEDRES | SVARM 2014
Sales data in this chapter originates from two different sources: 1) antibiotics sold by requisitions to acute care hospitals only, Swedish acute care hospitals, for a more detailed analysis and 2) all antibiotics sold by requistions, below mentioned as hospital care, gives a general view over usage and trends. Hospital care includes data from all Swedish acute care hospitals as well as data from those nursing homes and other care givers that order their antibiotics through requisitions. It varies between nursing homes if they buy antibiotics through requisition or by prescriptions to individual residents. If antibiotics are bought on prescription, data are included in primary health care data, presented in the previous section. The way of retrieving antibiotics to nursing homes varies among counties, but on a national level the proportion of antibiotics in hospital care sold to acute care hospitals is about 75%. In some counties almost 100% of all antibiotics are bought by acute care hospitals and in other counties this proportion is as low as 60%.
not change during the last year, and the consumption was at almost the same level as in 2013. Beta-lactamase resistant penicillins, fluoroquinolones, penicillins with enzyme inhibitor and carbapenems continue to increase as in previous years. The use of penicillins with enzyme inhibitor have increased substantially during the latest years, while the use of carbapenems has increased marginally. These agents have in many situations replaced the cephalosporins. Piperacillin with tazobactam accounts for the majority of the sales of penicillins with enzyme inhibitor (J01CR) in acute care hospitals. In 2014 penicillins with enzyme inhibitor increased
Figure 1.23. Antibiotic groups often used within hospital care 20002014, DDD/100 patient-days in Swedish acute care hospitals. 16 14 DDD/100 patient-days
Antibiotics in hospital care
Antibiotic consumption in Swedish acute care hospitals When analyzing data from acute care hospitals, there has been an increase in sales over the last five years (2010-2014) of 19% measured by DDD/100 patient-days and 10% measured by DDD/100 admissions. In 2014, the total consumption slightly increased compared with 2013, Table 1.3 and 1.4. Figure 1.23 shows the most frequent groups of antibiotics used in hospital care. The consumption of betalactamase sensitive penicillins, cephalosporins and aminoglycosides did
12 10 8 6 4 2 0
2010
2011
2012
Betalactamase resitant penicillins (J01CF) Fluoroquinolones (J01MA) Combinations of penicillins (J01CR) Aminoglycosides (J01GB)
2013
2014
Betalactamase sensitive penicillins (J01CE) Cephalosporins (J01DB-DE) Carbapenems (J01DH)*
*Includes all sales on requisition
Table 1.3. DDD/100 patient-days in somatic medical care in Swedish acute care hospitals 2010-2014. 2010
2011
2012
2013
Tetracyclines (J01AA)
4.6
5.0
5.3
5.4
5.4
Penicillins with extended spectrum (J01CA)
6.0
6.5
6.9
7.5
7.7
Betalactamase sensitive penicillins (J01CE) Betalactamase resitant penicillins (J01CF)
2014*
6.7
7.2
7.6
7.6
7.5
10.9
11.3
12.0
13.1
13.5
Combinations of penicillins (J01CR)
3.3
3.8
4.4
5.5
5.9
Cephalosporins (J01DB-DE)
7.1
6.8
6.7
7.1
6.8
Carbapenems (J01DH)**
2.5
2.6
2.7
3.0
3.1
Trimethoprim (J01EA)
0.9
0.8
0.6
0.5
0.4
Trimethoprim with sulphonamides (J01EE)
2.1
2.3
2.3
2.5
2.5
Macrolides (J01FA)
0.9
1.1
1.0
1.0
1.0
Lincosamides (J01FF)
1.7
1.7
1.9
2.1
2.0
Aminoglycosides (J01GB)
1.1
1.2
1.3
1.2
1.3
Fluoroquinolones (J01MA)
6.1
6.2
6.3
6.6
6.9
Glycopeptides (J01XA)
0.8
0.9
0.9
1.0
1.0
Imidazole derivatives (J01XD)
1.3
1.2
1.1
1.3
1.1
Nitrofurantoin (J01XE)
0.4
0.5
0.5
0.5
0.6
Methenamine (J01XX05)
0.6
0.5
0.5
0.6
0.6
Linezolid (J01XX08) All agents (J01) *Denominator data from 2013. ** Includes all sales on requisition
0.1
0.1
0.1
0.1
0.1
57.4
59.8
62.9
67.2
68.2
31
32
SWEDRES | SVARM 2014
Table 1.4. DDD/100 admissions in somatic medical care in Swedish acute care hospitals 2010-2014. 2010
2011
2012
2013
2014*
Tetracyclines (J01AA)
21.5
22.7
23.4
24.1
24.0
Penicillins with extended spectrum (J01CA)
28.0
29.5
30.6
33.3
34.0
Betalactamase sensitive penicillins (J01CE)
31.3
32.8
33.8
33.5
33.2
Betalactamase resitant penicillins (J01CF)
51.0
51.4
53.4
58.2
59.9
Combinations of penicillins (J01CR)
15.6
17.4
19.5
24.4
26.2
Cephalosporins (J01DB-DE)
33.3
31.1
29.9
31.7
30.2
Carbapenems (J01DH)**
11.9
11.9
12.2
13.5
13.9
Trimethoprim (J01EA)
4.0
3.6
2.7
2.1
1.9
Trimethoprim with sulphonamides (J01EE)
9.9
10.3
10.2
11.0
11.0
Macrolides (J01FA)
4.1
4.9
4.2
4.5
4.4
Lincosamides (J01FF)
7.9
7.9
8.4
9.1
8.8
Aminoglycosides (J01GB)
5.0
5.3
5.7
5.4
5.6
Fluoroquinolones (J01MA)
28.3
28.3
28.1
29.2
30.4
Glycopeptides (J01XA)
3.7
4.1
4.1
4.5
4.5
Imidazole derivatives (J01XD)
6.0
5.4
5.1
5.7
4.7
Nitrofurantoin (J01XE)
2.0
2.1
2.1
2.4
2.5
Methenamine (J01XX05)
2.7
2.5
2.1
2.5
2.6
Linezolid (J01XX08) All agents (J01)
0.4
0.3
0.4
0.5
0.6
267.5
273.2
278.9
298.1
302.2
*Denominator data from 2013. ** Includes all sales on requisition
with 7.3% measured as DDD per 100 patient-days compared to 2013. The corresponding figure for carbapenemes was 3.3%, Figure 1.23. The increase of these substances is probably a result of an increased number of infections with ESBL. Invasive infections caused by ESBL-producing Escherichia coli and Klebsiella pneumonia have increased, but the proportion of pathogens resistant to third-generation cephalosporins causing invasive infections is still very low in an European and international perspective. To minimize the selection of ESBL producing bacteria, a decreased use of 2nd and 3rd generation’s cephalosporins is recommended in Sweden. Due to the decrease in the consumption of cephalosporins, the beta-lactamase resistant penicillins (J01CF) is since 2008 the largest group of antibiotics in Swedish hospital care. A large proportion of the use consists of surgical prophylaxis (even though the hospital use in Sweden to a large extent has gone from a multi-dose to a single-dose prophylaxis). The use of fluoroquinolones (J01MA) has been at almost the same level since 2008, and accounts for about 10% of all antibiotics in hospital care. According to available data, antibiotic consumption in Swedish acute care hospitals show a wide variation between the counties in the use of narrow-spectrum penicillins, ranging from 6% to 19% of the total hospital consumption measured as DDDs, Figure 1.24. There are, however, great differences in dosages of penicillin G between the counties. DDD is 3.6 g and in Sweden the dosage varies from 1g three times a day to 3g three times a day. Type of hospital and patient composition may also influence the statistic and should be taken into account when comparing these data.
Figure 1.24. Percentage of narrow spectrum penicillins (penicillin V and G, J01CE) of all antibiotics in Swedish acute care hospitals 2014, per county. Värmland Jönköping Västmanland Norrbotten Jämtland Västra Götaland Västernorrland Gotland Södermanland Skåne Halland Kalmar Örebro Dalarna Blekinge Västerbotten Kronoberg Gävleborg Stockholm Östergötland Uppsala 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% DDD
Uppsala, Stockholm, Västerbotten, Västra Götaland, Skåne, Östergötland and Örebro Counties have tertiary referral hospitals. The use of cephalosporins varied between 3.3% and 15.7%, and the corresponding figures for fluoroquinolones were 8.5% to 15.0%, and 5.5% to 13.1% for piperacillin-tazobactam, and 2.4% to 7.8% for carbapenems, Figure 1.25 and Table 1.5. Taken together, the percentage of broad spectrum antibiotics (fluoroquinolones, cephalosporins, piperacillin with tazobactam and carbapenems) of all antibioitcs in Swedish acute care hospitals varied from 28.6 percent in Värmland County to 37.6 percent in Östergötland County, Table 1.5.
SWEDRES | SVARM 2014
Table 1.5. Percentage DDD of broad spectrum antibiotics (piperacillin with tazobactam, carbapenems, fluroquinolones and cephalosporins) of all antibiotics in Swedish acute care hospitals 2013-2014, per county. Piperacillin with tazobactam (J01CR05)
Carbapenems (J01DH)*
Fluoroquinolons (J01MA)
Cephalosporins (J01DB-DE)
All broad spectrum agents
2013
2014
2013
2014
2013
2014
2013
2014
2013
2014
Södermanland
7.8%
9.0%
2.7%
2.4%
14.6%
15.0%
3.9%
3.3%
29.3%
28.6%
Stockholm
5.7%
6.0%
4.6%
4.4%
9.9%
9.8%
11.1%
11.0%
29.1%
28.8%
Östergötland
4.9%
5.5%
4.3%
4.5%
9.1%
8.6%
16.1%
15.7%
27.6%
29.2%
Skåne
5.0%
5.7%
2.7%
2.8%
8.9%
9.1%
11.3%
11.5%
27.9%
30.0%
Västra Götaland
6.9%
7.5%
2.6%
3.3%
8.9%
8.8%
8.7%
8.2%
30.2%
30.4%
11.3%
13.1%
5.6%
5.9%
9.5%
9.1%
6.6%
10.0%
28.4%
30.8%
Norrbotten
7.7%
8.7%
4.2%
4.8%
8.5%
8.5%
7.1%
7.5%
29.5%
31.1%
Gotland
4.9%
7.0%
4.8%
3.9%
9.1%
8.5%
8.7%
9.5%
31.1%
31.2%
Jönköping
1.7%
7.8%
4.0%
4.0%
3.6%
10.2%
16.8%
9.9%
31.4%
31.3%
Värmland
6.3%
6.7%
3.3%
2.9%
9.4%
9.4%
10.9%
10.0%
29.7%
31.4%
Örebro
6.2%
8.1%
3.9%
3.4%
12.0%
11.4%
10.3%
9.1%
31.9%
31.4%
Halland
4.7%
5.7%
3.1%
3.5%
9.4%
10.8%
11.0%
10.8%
25.1%
31.4%
Kronoberg
5.9%
6.9%
2.6%
4.0%
13.4%
13.4%
11.8%
10.6%
30.3%
32.1%
Uppsala
8.6%
9.4%
3.8%
3.6%
10.3%
10.8%
10.7%
9.9%
32.3%
32.2%
Västerbotten
6.1%
5.7%
4.9%
4.4%
10.6%
10.3%
11.3%
12.0%
32.0%
32.4%
Blekinge
6.2%
6.9%
5.8%
5.6%
10.3%
10.3%
11.3%
10.9%
32.4%
32.4%
Västmanland
6.8%
7.7%
3.6%
3.7%
12.7%
3.4%
6.9%
7.3%
32.8%
33.3%
Västernorrland
5.8%
6.7%
3.0%
4.0%
11.9%
12.5%
11.6%
10.4%
34.6%
33.8%
Jämtland
6.6%
7.9%
3.6%
3.2%
11.4%
10.8%
9.5%
8.5%
34.7%
34.1%
Dalarna
4.9%
5.9%
4.8%
6.1%
11.7%
11.9%
10.6%
10.2%
34.4%
36.2%
Gävleborg
7.6%
8.2%
8.0%
7.8%
11.3%
10.6%
12.7%
11.1%
38.1%
37.6%
Kalmar
* Includes all sales on requisition
0%
10% 20% 30% 40% 50% 60% 70% 80% 90% 100% DDD Fluoroquinolones Cephalosporins Piperacillin with Carbapenems (J01MA) (J01DB-DE) tazobactam (J01CR05) (J01DH)* *Includes all sales on requisition
0,35 0,30 0,25 0,20 0,15 0,10 0,05
*Includes all sales on requisition
2013
2014
2012
2011
2009
2010
2007
Beta-lactamase resistant penicillins (J01CF) Fluoroquinolones (J01MA) Combinations of penicillins (J01CR) Aminoglycosides (J01GB)
2008
2006
2005
2003
2004
0,00 2001
Värmland Västra Götaland Norrbotten Halland Jämtland Gotland Skåne Södermanland Kalmar Västmanland Västerbotten Jönköping Blekinge Örebro Dalarna Stockholm Västernorrland Gävleborg Kronoberg Uppsala Östergötland
Figure 1.26. Antibiotic groups often used within hospital care 20002014, DDD/1 000 inhabitants and day.
2002
Figure 1.25. Percentage of broad spectrum antibiotics (fluoroquinolones, cephalosporins, piperacillin with tazobactam and carbapenems) of all antibiotics in Swedish acute care hospitals 2014, per county.
Figure 1.26 is the same as Figure 1.23, the difference is only that this includes all sales on requisition (hospitals, nursing homes and other units order of antibiotics on requisition). The figure shows the clear shift from high use of broad spectrum antibiotics to narrow spectrum antibiotics. The consumption of cephalosporins, fluoroquinolones, aminoglycosides and vancomycin did not change during the last year. Beta-lactamase resistant penicillins, penicillins with enzyme inhibitor and carbapenems continues to increase like previous years.
2000
The total antibiotic sale on requisition has increased in Sweden during 2000-2007 and has since then been on a quite stable level. During the last year the consumption did not change and the levels for 2014 corresponds with those in 2013. Even though we have not seen any increase since 2012, the consumption has still increased with 33% since the year 2000, from 1.18 to 1.60 DDD/1 000 inhabitants and day, Table 1.6.
DDD/1000 inhabitants and day
Antibiotic consumption in hospitals
Beta-lactamase sensitive penicillins (J01CE) Cephalosporins (J01DB-DE) Carbapenems (J01DH)* Vancomycin (J01XA01)
33
34
SWEDRES | SVARM 2014
The “Anti-infection Tool” has previously been presented in Swedres-Svarm 2013. It is a national IT support tool for surveillance of healthcare-associated infections and the use of antibiotics. Every time antibiotics are prescribed through the electronic medical record system the doctor is forced to indicate the reason for the prescription. In addition, data is also transferred back from the patient´s medical record to the “Anti-infection Tool”, providing information on diagnoses, microbiology results (only for C. difficile) and other medical procedures. Since 2014, the “Anti-Infection Tool” is fully implemented in practically every Swedish hospital. Through the reporting tool it is easy to get an exact overview of the usage of different antibiotics in each specific unit in the hospital. A validation study in Kalmar County shows that the quality of registrations differs between the predetermined diagnoses, however, the impact of error in registration decrease over time. It is important to keep in mind that the present version of the tool doesn´t measure the total amount of antibiotics used, just the type of antibiotic.
Example from Kalmar County At the three hospitals in Kalmar County, the Antiinfection Tool was introduced during the summer 2013. Below you will find examples on how the “Anti-infection Tool” has been implicated in small clinical projects by the local Strama (the Swedish Strategic Programme against Antibiotic Resistance) group in Kalmar County. In Kalmar County, urinary tract infections without fever is the most common indication for antibiotic treatment in hospitals. In addition, the prevalence of asymptomatic bacteriuria increase with rising age, especially among women. Tiredness, occasional confusion and other diffuse symptoms are often misinterpreted as symptoms of urinary tract infection. In combination with signs of bacteria in the urine this often leads to unnecessary antibiotic treatment. The ”Anti-infection Tool” easily identifies wards with a questionable high use of antibiotics among elderly women with this diagnosis. In Kalmar County, three wards with high consumption were identified, and data was confirmed by examination of the patients’ medical records. The results were pre-
Figure A. Number of patients treated with antibiotics for the indication urinary tract infection without fever at the geriatric clinic in Kalmar County (July 2013- December 2014). The intervention was started in quarter 4 2013 (November), marked with red arrow in the figure. Number of patient treated with antibioitcs for the indication UTI without fever
In focus
A national IT tool for surveillance of healthcare-associated infections and antibiotic use
25 Start of intervention
20
15
10
5
0 2013-Q3
2013-Q4
2014-Q1
2014-Q2
2014-Q3
2014-Q4
sented for the ward staff together with a short lecture on the subject. The use of antibiotics for urinary tract infections has decreased at the identified wards since the start of the intervention, Figure A. In the reporting tool, there is a function which gives access to the personal identity numbers of the patients contributing to the statistics, facilitating a deeper analysis through the medical record. The Strama group in Kalmar County looked at the diagnostic quality in the emergency unit. The aim of the project was to evaluate if the preliminary diagnosis of pneumonia reported to the ”Anti-Infection Tool” correspond to the final diagnosis, i.e was it safe to always start with narrow spectrum antibiotic such as bensylpenicillin on these patients? A selected population on 20 patients who received narrow spectrum antibiotics on admission were included in the project. One of the patient were later diagnosed with pyelonephritis, however, the rest did not change from pneumonia. One patient required a broader antibiotic after 3 days. The results shows that it was safe to start with narrow spectrum antibiotics for the preliminary diagnosis pneumonia. In Kalmar County bensylpenicillin was the most used antibioitc for community-acquired pneumo-
nia, Figure B. However, Piperacillin/tazobactam was the second most commonly used antibiotic. The results from the project mentioned above indicates that there might be an opportunity for improvement regarding choice of antibiotics for treatment of mild-moderate severe community-acquired pneumonia in Kalmar County. Another area of application is as part of antibiotic stewardship by infectious disease consultants. From the tool the consultant can get information about all patients who have started a certain antibiotic treatment within the entire county. Based on the information in the medical record the infection specialist, working at any hospital in the county, could write a recommendation to all hospitals on what antibiotic to use in a particular patient. The aim would be to identify unnecessary treatment with broadspectrum antibiotics and to advice on further infection treatment strategies. The ”Anti-infection Tool” has great potential for development and the quality in registration by the doctors can be improved. Yet it is already a valuable tool for optimizing antibiotic treatment in hospitals. The future challenge is to engage more clinicians in the use of this tool.
Figure B. Antibiotics prescribed for the indication community-acquired pneumonia in emergency unit in Kalmar County during July 2013 to December 2014. 200 180 160 Number of ordinations
140 120 100 80 60 40 20
[J n
llin
illi Be
ns
yl
pe
ni
ci
ox ic
*[J01DB05, J01DD02, J01DD14, J01DH02, J01EA01, J01EE01, J01MA02 and J01MA14]
* er th O
04 ] (p en [J ici 01 llin Pe CE G ni 01 ) vi llin ] V [J 01 CE Cl 02 ox ac ] illi n Am [J 0 ox 1C ic F0 in illin 2] hi w bi to ith r Pi [J en 01 zy pe CR m ra ci 02 e in llin hi w ] bi to ith r[ e J0 nz Ce 1C ym fo R0 e ta 5] xi m [J 01 Er yt D D hr 01 om ] yc in [J 0 Cl 1F in A0 da 1] m yc in [J 01 G FF en 01 ta m ] ic in [ J Le 01 vo G B0 flo 3] xa ci n [J 01 M A1 2]
CA 01
01 Am
ci pi Am
D
ox
yc
yc
lin
llin
[J
[J
01
AA 02
]
CA 01 ]
0
35
In focus
SWEDRES | SVARM 2014
SWEDRES | SVARM 2014
Table 1.6. Antibiotic consumption in hospital care 2000-2014, DDD/1 000 inhabitants and day. 2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
J01 excl methenamine
1.18
1.22
1.25
1.33
1.36
1.43
1.49
1.55
1.52
1.48
1.52
1.59
1.63
1.60
1.60
Methenamine (J01XX05)
0.03
0.03
0.02
0.05
0.07
0.07
0.07
0.07
0.05
0.03
0.03
0.02
0.02
0.02
0.02
J01
1.21
1.25
1.27
1.37
1.43
1.50
1.56
1.62
1.57
1.52
1.55
1.61
1.65
1.62
1.62
Figure 1.27 shows that the consumption of cephalosporins increased until 2006 when it peaked. After 2006 there has been a drastic change, and between 2006 and 2014 the consumption of cephalosporins decreased by 50% from 0.26 to 0.13 DDD per 1 000 inhabitants and day. Consumption of 3rd generation cephalosporins, mainly cefotaxim and ceftazidime, have replaced the use of 2nd generation cephalosporins (cefuroxime). The decrease in DDD can partly be explained by the shift from cefuroxime to cefotaxime, since the previously recommended standard doses do not conform to the WHO definitions. In Sweden, the previously recommended standard doses of cefuroxime was 1.5g x 3 = 4.5 g/d and cefotaxime 1g x 3 = 3 g/d compared to the WHO definition of DDD; 3 g/day and 4 g/day respectively. The overall decrease in the consumption of cephalosporins in hospital care indicates that these substances has been replaced by other antibiotics. The Strama network, together with local drug and therapeutic committees have promoted the following changes in antibiotic policy in Swedish hospitals: 1) moderately severe (CRB-65 0-1) community acquired pneumonia (CAP) should be treated with narrow-spectrum penicillins; 2) surgical prophylaxis should normally be given as one dose except in high-risk situations where 24 h is a maximum with few exceptions; 3) uncomplicated lower urinary tract infections in women should be treated with pivmecillinam or nitrofurantoin, including hospital inpatients, whereas the use of fluoroquinolones should be restricded; 4) extended-spectrum cephalosporins and fluoroquinolones should not be used in situations where treatment with a narrow-spectrum penicillin is an alternative (Hanberger H et al., 2014). This can be reflected in the statistic.
Adverse reactions related to antibiotic use Reported drug-related adverse reactions are continuously entered into BiSi, a national database administered by the Swedish Medical Products Agency. The reports originate from health care professionals. The antibiotic related adverse reactions during the last five years, 2010-2014, were analysed for various groups of agents. The following organ system groups received most reports related to the use of systemic antibiotic drugs (J01): skin- and subcutaneous tissue disorders (n=829), gastrointestinal disorders (n=273), hepatobiliary disorders (n=99), general disorders (n=149), blood disorders (n=86), neurological reactions (n=116), respiratory disorders (n=106), immune system disorders (n=130), musculoskeletal disorders (n=81), psychiatric disorder (n=50) and renal and urinary disorders (n=67). The majority of the reports (57%) concern female patients, which is corresponding to the gender difference seen in the antibiotic use. The 10 antibiotic substances most commonly associated with adverse reactions, in the last 5 years unadjusted for consumption and regardless of the cause of the report are presented in Table 1.7. We have previously reported that amended treatment recommendations resulted in changed prescription patterns for uncomplicated urinary tract infections. Due to the low number of reports and to the fact that data are based on spontaneous reporting, no clear conclusions can be made regarding these trends, Table 1.8.
Table 1.7. Most reported adverse drug reactions related to antibiotic agents to the Swedish Medical Products Agency 2010-2014. Figure 1.27. Cephalosporins in hospital care, 2000-2014, DDD/1 000 inhabitants and day.
Antibiotic
0,3 0,25 0,2 0,15 0,1
1st gen. cephalosporins (J01DB) 3rd gen. cephalosporins (J01DD)
2013
2014
2011
2012
2009
2010
2007
2008
2006
2005
2003
2004
2001
0
2002
0,05 2000
DDD/1000 inhabitants and day
36
2nd gen. cephalosporins (J01DC)
Total number of adverse drug reaction reports
Number of ’serious’ reports
Number of fatal cases
Ciprofloxacin
202
114
2
Flucloxacillin
180
115
7
Phenoxymethylpenicillin
158
70
0
Sulfamethoxazole and trimethoprim
130
80
1
Clindamycin
121
70
2
Nitrofurantoin
120
73
2
Amoxicillin
99
43
0
Doxycycline
92
43
0
Cefotaxime
88
41
1
Piperacillin and enzyme inhibitor
82
43
0
SWEDRES | SVARM 2014
Table 1.8. Number of most frequently spontaneously reported adverse events for fluoroquinolones and nitrofurantoin, during the period 2010 – 2014. 2010
2011
2012
2013
2014
20102014
28
25
19
28
46
146
3
3
4
10
12
32
tendinitis
3
2
3
3
1
12
tendon rupture
2
3
3
3
1
12
Skin- and sub cutaneous tissue
11
5
4
5
13
38
5
4
0
7
7
23
24
25
30
20
21
120
Fluoroquinolones (J01MA) Total no of reports Number of reactions Musculoskeletal
Psychiatric disorders Nitrofurantoin (J01XE01) Total no of reports Number of reactions
6
4
16
8
7
41
dyspnoea
3
1
4
5
4
17
interstitial pneumonia
2
0
2
1
0
5
Respiratory system
pulmonary fibrosis Skin- and
0
0
3
0
3
6
10
10
17
6
4
47
7
6
3
10
2
28
3
3
2
4
1
13
subcutaneous tissue General disorders Fever
Consumption of systemic antifungals Hospital care Compared to 2013 the total consumption of antifungal drugs for systemic use is unchanged, with a national average of 61 DDD per one million inhabitants and day. Every year since 2000 except for 2011 and 2014 there has been a small but steady increase. Since the year 2000 when the total consumption was 40 DDD per one million inhabitants and day, the increase has been 50%. Meanwhile there has been a 38% increase in the consumption of antibiotics in hospital care for the same period. Compared to other European countries the Swedish consumption of antifungals is slightly below the EU median (83 DDD per one million inhabitants and day, 2011) (European Centre for Disease Prevention and Control, 2014). The figures vary between the different counties. Uppsala and Västernorrland, both counties with tertiary referral hospitals, have the highest consumption with an average of 149 DDD per one million inhabitants and day. Historically those two counties have had the highest consumption since 2000. The lowest use was in Jönköping County with 12 DDD per one million inhabitants and day. Fluconazole still constitutes the majority of the antifungals consumed, 65% or 39.5 DDD per one million inhabitants and day. Amphotericin B is the second most consumed compound. The consumption increased 28% compared to
2013, and now stands for 16% of the total consumption in 2014. The trend since 2000 shows that most of the described increase is due to an increased use of fluconazole. In the year 2000 the fluconazole consumption was 30 DDD per one million inhabitants and day, representing 74% of the total consumption. Fluconazole is a narrow spectrum antifungal with effect towards Candida species (excluding among others Candida krusei and most strains of Candida glabrata). It is a fungiostatic drug that is indicated for treatment of invasive non krusei, non glabrata candidosis in non neutropenic patients and for cryptococcosis. It is also used as prophylaxis against candida infection and as treatment for local infections such as thrush. Among antifungals with a broader spectrum, including both Candida glabrata and Aspergillus sp two new classes of antifungals have been introduced since 2000; the echinocandins and azoles with an enhanced efficacy. The echinocandins as a group today stands for 12% of the total consumption. Amphotericin B that in the year 2000 was the only broadspectrum antifungal available and then constituted 20% of the total consumption, remains an important compound with todays 16%. Among the azoles with broadspectrum there has been a shift from itraconazole that in 2000 represented 3% of all antifungals to voriconazole and posaconazole that in 2014 stands for 7.5% of the total consumption. In 2014 itraconazole was hardly used at all. The new azoles; voriconazole which is regarded as treatment of choice for proven or probable aspergillosis, and posaconazole, increasingly used as prophylaxis against invasive fungal infection in certain high risk neutropenic patients, both have good effect against the most common candida species with the possible exception of C. glabrata, which is an emerging pathogen in Sweden and now constitutes approximately 20% of all episodes of candidemia. C.krusei is always resistant. The consumption of voriconazole is low in absolute numbers (1.83 DDD per one million inhabitants and day), and is virtually unchanged since last year. Voriconazole is the only broad-spectrum antifungal drug that can be given orally and is therefore often used when the initial iv therapy is switched to oral, even in those cases when therapy was started with an echinocandin or amphotericin B. It is also used as secondary prophylaxis against aspergillus infections. The total sales of voriconazole in outpatient settings is almost three times higher than in hospital care (4.5 DDD per one million inhabitants and day). However, since the absolute majority of voriconazole therapies is initiated and monitored by hospital physicians, it is probably more correct to confer those data to hospital use rather than primary health care use. The amount of voriconazole on prescription have slightly decreased compared to previous years. Posaconazole can also be given orally, but in Sweden it is only licensed as second line therapy for invasive fungal infection refractory to the first line treatment and as prophylaxis, so it is mainly used as prophylaxis in hematologic units. During 2014 a new formula was released, enterocapsule, which will have an improved resorption and the increased
37
SWEDRES | SVARM 2014
In outpatient care Seventy-eight percent of all systemically administrated antifungal drugs are sold on prescription. The majority of those prescriptions took place in primary health care. The most commonly prescribed drug is fluconazole (86%), mainly for mucocutaneus infections. There are many different topical applications containing imidazoles, with or without steroids, mainly used for dermatophyte infections of the skin or vaginal yeasts infections. Some of those are sold on prescription and others are available as OTC drugs for self-medication.
Figure 1.28. Sales of broad spectrum antifungals in hospital care 2009-2014. DDD/1 000 inhabitants and day.
0,0080 0,0060 0,0040
gi n ni du -a
5
-c
2012
6 X0 2A J0
J0
2A
X0
4 X0 2A J0 2011
la fu n
gi n -m ic a
po as
ac os -p 4 C0
2A J0
2010
fu n
fu n
az on
na or ic o -v 3
C0 2A
ol e
le zo
in ot er ac m ph -a J0
1 A0
2009
gi n
0,0020
b
DDD/1000 inhabitants and day
0,0100
2A
use in 2014, up 32% from 2.2 DDD per one million inhabitants and day to 2.9 DDD per one million inhabitants and day might be explained by this novelty and 5.9 DDD per one million inhabitants and day are sold in outpatients settings. As for voriconazole it is probably more correct to confer all data to hospital use. Since 2005 there has been a small but steady increase in the consumption of the echinocandins. In 2014 the consumption increased by 11%, making the total amount 7.3 DDD per one million inhabitants and day, and the group now constitutes 12% of all systemic antifungals consumed in hospitals. Caspofungin which has been available in Sweden since 2002 has seen its market share diminish for every year. It now constitutes 44% of the echinocandins. Anidulafungin increased its share from 30% to 38% last year. The third member of the group micafungin that for the first time appeared in the statistics in 2012 now constitutes 18%. There are no evidence for a shift in the distribution of, or in the pattern of resistance among invasive candida species in Sweden. The increased use of both anidulafungin and micafungin is probably due to their lower cost. The new indication for anidulafungin – empiric treatment of patients with neutropenia and fever – has probably resulted in an increased use of anidualfungin. Early preclinical trials of micafungin indicated an increased risk of livertumor among rats. An extended worldwide use of the compound has not showed an increased risk among humans, but the EMA still issues a warning label. The echinocandins have a fungicide effect against candida species and a fungiostatic effect against Aspergillus fumigatus. Therefore those agents are increasingly used as first line therapy for patient with febrile neutropenia when antibiotics alone have not been successful and when there is a suspicion of infection with yeasts or mold. Amphotericin B has for a long time been considered the golden standard for treatment of invasive fungal infection due to its broad spectrum and well documented effect against most yeasts and molds. However the tolerability is a problem. Side effects are common with nephrotoxicity and electrolyte imbalance as the most severe. Therefore amphotericin B is now mostly used in its liposomal form, which improves tolerability. Since 2009 there has been an increased use of amphotericin B for five out of six years. Last year’s increase was 28%, and amphotericin B now constitutes 44% of all broad spectrum antifungal use, Figure 1.28.
J0
38
2013
2014
Data comparing sales of antimycotic drugs between different countries are rare but recently ESAC published comparative data from different European countries, showing that the Swedish figures of sales are comparably low (European Centre for Disease Prevention and Control, 2014).
Consumption of antibiotics in animals Statistics on total consumption of antibiotics for use in animals in Sweden are available since 1980. For a review of data from 1980-2000, see Svarm 2000 and for the follwing years the relevant Svarm- and Swedres-Svarm-reports. Data are derived from sales statistics. In the following, the term consumption will be used for sales from pharmacies to private and professional animal care-takes as well as to veterinary clinics. The consumption represents an approximation of the use of antibiotics, assuming that the amount sold is also used during the observation period. Details on data source and inclusion criteria are given in Materials and methods, consumption of antimicrobials.
Completeness of data Until 2009, statistics on consumption of antibiotics was assumed to be complete. Since, the Swedish pharmacy market has been reregulated and concerns have been raised that data on consumption of veterinary medicinal products with a general marketing authorisation from recent years are less complete than before the reregulation. It is assumed that the problem mainly or only concerns products sold on requisition to veterinarians (i.e. for use in their practice), mostly injectables. Expressed as kg active substance, sales to pharmacies were 8% higher than from pharmacies for 2013 and 14% higher for 2014. For further information on the lack of completeness of data from recent years, see Materials and methods, consumption of antimicrobials. Most of the trends identified in the data presented below have been observed before 2010. There are known expla-
SWEDRES | SVARM 2014
nations relating to e.g. changes in prescribing behaviour or improved animal health that support the view that there is a true decrease in antibiotic consumption. The exception is sales of benzylpenicillin where sales have decreased from 2010. The latter trend is corroborated by data from other sources indicating a true decrease (see Comments on trends by animal species, Dairy cows). Taken together, the lack of completeness of data from 2010 should be kept in mind when interpreting the data from recent years. From 2010 and onwards the magnitude of the changes cannot be assessed for classes with injectable products. Products for oral medication of individuals or groups are not likely to be affected to a significant degree.
Trends in animal populations Changes in the numbers of animals may affect trends in statistics on consumption of antibiotics. The number of pigs slaughtered has decreased by 13% in five years, while the number of broilers was 14% higher in 2014 than in 2010. The number of dairy cows has been unchanged over the same timeperiod. The number of horses was 349 000 in 2010. The number of dogs was 784 000 in 2012 and 729 000 in 2006. Further details on animal numbers are found in Demographics and denominator data.
Overall consumption Of the overall consumption expressed as kg active substance, about 90% are products formulated for treatment of individual animals (injectables, tablets, intramammaries) and about 10% for treatment of groups or flocks (premixes, oral powders, solutions for in water medication). In 2014, the total reported sales from Swedish pharmacies of antibiotics for animals were 10 271 kg, of which 53% was benzylpeni-
cillin. The corresponding overall figures for 2005 and 2010 were 16 389 kg and 14 117 kg, respectively. When interpreting the figures, the mentioned decrease in numbers of pigs slaughtered as well as the uncertainty of data from recent years must be borne in mind. Still, there is most likely a true decrease over time but as data from recent years are uncertain its magnitude cannot be estimated. Because of the indications of lack of completeness discussed above, more detailed data on overall consumption of antibiotics (e.g. by class) are not presented in this report. Information on overall consumption previous years can be found in Swedres-Svarm 2013 and earlier reports.
Consumption of antibiotics for parenteral use The consumption of antibiotic products formulated for injection is presented in Table 1.9. Trends from 2010-2014 are uncertain as there is a lack of completeness in data (see Completeness of data). In January 2013, a regulation limiting veterinarians’ right to prescribe fluoroquinolones and third and fourth generation cephalosporins entered into force (SJVFS 2013:42). Antibiotics in these classes may only be prescribed for animals if a microbiological investigation shows that alternative choices cannot be expected to be effective. Exceptions are for example acute life threatening infections. Unfortunately, for reasons explained above, the magnitude of the effect of the regulation cannot be assessed directly from the consumption data.The decrease in consumption, however, of these antibiotics is larger than the estimated lack of completeness. Further, an increase in consumption of trimethoprimsulphonamides from 2012 to 2014 probably reflects a switch to this class in situations when fluoroquinolones would have been used before the regulation.
Table 1.9. Yearly consumption of antibiotic drugs for parenteral use (injections), expressed as kg active substance and proportion sold on requisition to veterinarians. Figures are uncertain because of indications of lack of completeness. ATCvet code
Antimicrobial class
QJ01AA
Tetracyclines
QJ01BA
Amphenicols
QJ01CE, -R, QJ51
Benzylpenicillin
2006
2007
2008
2009
2010
2011
2012
2013
2014
Percent sold on requisition 2014
564
588
557
527
492
471
422
424
396
53
0
3
7
4 63
7 778
7 505
7 674
7 641
7 492
6 627
6 290
5 901
5 455
QJ01CA, QJ01CR
Aminopenicillins
134
142
143
152
144
146
143
131
145
34
QJ01DD
Cephalosporins
26
26
25
21
13
13
8
4
2
63
QJ01G, -R
Aminoglycosides
345
343
318
301
272
246
210
104
145
44
QJ01E
Trimethoprim & sulphonamides
804
685
691
669
685
667
699
857
849
30
QJ01F
Macrolides & lincosamides
241
216
136
118
101
95
95
95
90
3
QJ01MA
Fluoroquinolones
132
125
118
113
105
83
69
29
25
73
QJ01XX92, - 94
Pleuromutilins
39
36
36
28
17
13
14
17
13
6
10 064
9 666
9 699
9 568
9 322
8 362
7 950
7 565
7 125
57
Total
39
40
SWEDRES | SVARM 2014
Table 1.10. Yearly consumption of antibiotic drugs for oral medication of individual animals, expressed as kg active substance and proportion sold on requisition to veterinarians. ATCvet code
Antimicrobial class
QJ01AA
Tetracyclines
QJ01CA, QJ01CR
Aminopenicillins
QJ01DB
Cephalosporins
QA07AA
Aminoglycosides
2006
QA07AB, QJ01E
Trimethoprim & sulphonamides
QJ01FF
Lincosamides
QJ01MA
Fluoroquinolones
Total
2007
2008
2009
2010
2012
2013
2014
Percent sold on requisition 2014
45
44
47
48
46
50
47
38
1
775
756
681
650
598
501
500
460
3
1 186
924
792
714
562
402
325
297
2
131
126
131
118
109
102
77
61
12
2 189
2 179
2 028
1 838
1 670
1 442
1 169
1 164
24
176
194
216
214
210
178
164
159
2
59
52
46
46
39
32
22
18
5
4 559
4 276
3 941
3 630
3 234
2 706
2 304
2 198
14
Consumption of antibiotics for oral medication of individual animals
Consumption of antibiotics for oral medication of groups of animals
In Table 1.10, the sales of products formulated for oral medication of individual animals are presented. For this category, the completeness of data is likely to be high and trends can be assessed. For all classes except trimethoprim-sulphonamides and aminoglycosides, this category of antibiotics consists of tablets sold for companion animals. The aminoglycosides also include products authorised for farm animals while the trimethoprim-sulphonamides are mostly products for horses. The sales of fluoroquinolones have decreased gradually since 2006 (- 69%). A more pronounced decrease is noted from 2012 to 2014 (- 43%). This is probably a reflection of the above mentioned regulation restricting veterinarians’ prescribing of fluoroquinolones. Major downward trends from 2010-2014 are noted for all classes. For further comments see Comments on trends by animal species, Horses and Dogs.
Data on consumption of antibiotics formulated for medication of groups of animals are given in Table 1.11. Data for 1984 are given as historical reference. As for products for oral medication of individual animals, completeness is likely to be high. Today, the consumption of products for medication of groups of animals are less than 10% of what it was on average before 1986 (counting the sum of veterinary medicines and growth promoters). Products for medication of groups of animals are mainly for treatment of pigs. There has been an overall decrease by 55% of consumption of such products since 2010 (Table 1.11). The consumption of pleuromutilins has decreased since the mid 90s and were 64% lower in 2014 than in 2010. The main indication for pleuromutilins (tiamulin, valnemulin) is swine dysentery. Efforts to control the disease through e.g. eradication from affected farms and a certification programme have resulted in a decreased need to treat swine
Table 1.11. Yearly consumption of antibiotic drugs authorised for group treatment and ionophoric anticoccidials sold expressed as kg active substance. ATCvet code
Antimicrobial class
QA07A
Intestinal anti-infectives
QJ01A
Tetracyclines
QJ01C
Penicillins incl. aminopenicillins
QJ01F
Macrolides & lincosamides
QJ01MA
Fluoroquinolones
QJ01MQ
Quinoxalinesb
9 900
QJ01XX91
Streptograminsc
8 800
QJ01XX92, -94
Pleuromutilins
QP51AA
Nitroimidazoles Feed additivesd
Total QP51AH
Ionophoric antibiotics (coccidiostats)d
1984
12 300
607
2004
712
2005
2006
2007
2008
2009
2010
2011a
2012
2013
2014
163
170
158
106
107
119
77
75
76
80
934
903
1 217
1 040
594
575
552
408
463
352
11
28
111
266
164
36
5
13
30
713
680
837
1 107
744
657
427
361
359
305
235
7
5
5
3
5
5
4
2
6
1
2
355
309
420
471
536
370
157
127
85
109
101
33 747
1 787
2 091
2 346
2 984
2 543
1 999
1 447
1 154
937
968
800
7 900
10 486
11 095
12 335
12 527
13 376
12 471
15 325
14 693
12 860
12 489
14 194
1 440 700
For some classes, data on sales of products sold with special licence may be incomplete for 2011 (indicated in red). Drugs with special licence prescription include colistin, tetracyclines, aminopenicillins and small quantities of benzylpenicillin; b Years 1980-1984 sold as feed additives, thereafter on veterinary prescription at therapeutic dosages until 1997; c Feed additives other than quinoxalines and streptogramins: avoparcin, bacitracin, nitrovin, oleandomycin and spiramycin; d Figures are from the Feed control of the Board of agriculture (www.sjv.se) a
SWEDRES | SVARM 2014
dysentery, reflected in overall declining consumption figures. The continued drop in consumption of macrolides for group medication (55% lower in 2014 than in 2010) is likely to reflect improved knowledge on how to manage problems with concomitant infections in herds with postweaning multisystemic wasting syndrome and the introduction of vaccination strategies.
Consumption of antibiotics for intramammary use In 2014, a total sales from pharmacies of 79 790 dose applicators for use in lactating cows were reported. The two products on the Swedish market contain either procaine benzylpenicillin or procaine benzylpenicillin combined with dihydrostreptomycin. The sales of intramammary products for use at drying off were 231 520 dose applicators in 2014. The two products on the Swedish market contain prodrugs of benzylpenicillin combined with either framycetin or dihydrostreptomycin. The figures above include only products with general marketing authorization. In addition a limited number of dose applicators with special marketing authorization were sold.
Comments on trends by animal species Dairy cows Växa Sweden publishes a yearly report related to the livestock organisations’ work to improve animal health and welfare in dairy cows (Växa Sverige, 2014). For statistics on incidence of antibiotic treatments of dairy cows enrolled in the Swedish milk recording scheme, data are retrieved from a database with veterinary reported disease events and treatments (Jansson Mörk, 2010). According to Växa Sweden (2014), the by far most common indication for treatment of dairy cattle is mastitis; around 70% of all recorded treatments of cows. In Sweden, mastitis is generally treated systemically and any changes in treatment incidence, treatment length or choice of antibiotic for this condition will have a noticeable influence on the statistics on sales of antibiotics. The reported incidence of treatment of clinical mastitis in dairy cows has decreased over the last ten years and was 10.7 recorded treatments per 100 completed/interrupted lactations in 2013/2014. Treatment with benzylpenicillin was by far the most common (89%). As mentioned, a total of 231 520 dose applicators of intramammaries for use at drying off were sold from Swedish pharmacies in 2014. Assuming that all cows were treated in four teats, this corresponds to 57 880 treated cows. That figure has been stable over the last five years.
Pigs Antibiotics for pigs are mostly sold on prescription by pharmacies to the animal owner. Data are therefore not likely to be affected by the lack of completeness discussed above (see Completeness of data).
Table 1.12. Consumption of antibiotics for pigs in 2014 expressed as mg per kg slaughtered pig and percentage change since 2010. Individual medication Group medication Antimicrobial class
2014
Change since 2010 (%)
2014
Change since 2010 (%)
Aminoglycosides
0.23
-38
Aminopenicillins
0.38
Amphenicols
0.01
-15
0.08
-75
Cephalosporins 3gen
0.00
Fluoroquinolones Macrolides & lincosamides
0.01
-79
0.00
0.36
9
0.89
-37
Benzylpenicillin
5.51
10
Pleuromutilins
0.05
-22
0.43
-29
Polymyxins Tetracyclines
0.34
45
Trimethoprimsulphonamides
2.32
26
Total
9.23
12
0.34
-5
1.29
-30
3.03
-33
In 2010 and 2014 the consumption of antibiotics for pigs was 3 369 and 2 883 kg active substance, respectively, or 12.8 and 12.3 mg/kg slaughtered pig. Of the total consumption in kg active substance during 2014, 75% were products for injection, and of those 60% were products containing benzylpenicillin. The consumption of fluoroquinolones for pigs was 3.2 kg and there was no consumption of third generation cephalosporins for pigs. In Table 1.12, the consumption of antibiotics for pigs expressed as mg per kg slaughtered pig is shown. The overall consumption has been stable over the last five years but the consumption of products for individual medication have increased and products for group medication have decreased (see Consumption of antibiotics for group medication). Benzylpenicillin is by far the most commonly sold substance (45% of the total, expressed as mg per kg slaughtered pig) and consumption has increased over time. Analysis of trends in consumption of antimicrobials for pigs between 2006 and 2010 (see Highlight in Svarm 2011) showed a similar pattern. A shift from products for medication of groups of animals via feed or water towards medication of individual animals, preferably with narrow spectrum substances such as benzylpenicillin is observed over the last ten years. This is well in line with guidance on appropriate use of antibiotics.
Poultry Antibiotics are rarely used for treatment of bacterial diseases in commercially reared Gallus gallus. Localized outbreaks can therefore have a major influence on the sales in a specific year. Over the last five years, the yearly sales of fluoroquinolones for slaughter chickens and hens have been below or much below 0.5 kg. Cephalosporins are never used. From 2011, the Swedish poultry meat association requests all treatments of broilers, parents and grandparents to be
41
SWEDRES | SVARM 2014
reported as part of the Poultry health control programme. According to the reports, a total of 4 of 3138 broiler flocks (0.13%) were treated with phenoxymethylpenicillin in 2014. This corresponds to 0.08 mg active substance/kg slaughtered chicken. In addition, 21 out of 249 grandpartent and parent flocks were treated with penicillins, mostly phenoxymethylpenicillin. Coccidiostats of the ionophore group are used as feed additives to control coccidiosis in the production of chickens for slaughter and for turkeys. Since the late 80s, narasin is by far the most widely applied substance for broilers.
Horses Around two thirds of the consumption of trimethoprim-sulphonamides are products for oral use in horses (paste or powder). The consumption of such products increased steadily until 2006 but from 2010, there has been a decrease by 29%. Among the indications for trimethoprim-sulphonamides in horses are reproductive disorders and various conditions in foals. Since 2009, the number of mares covered and number of foals born has decreased (Anonymous, 2014). Thus, it is probable that the decrease in consumption of trimethoprimsulphonamides is explained by the lower number of mares covered and a lower number of foals born. The consumption of other antibiotics for horses is difficult to estimate, as they are frequently sold on requisition and administered by the veterinarian in connection with an examination, either in ambulatory practice or in clinics or hospitals.
Dogs Data on outpatient consumption of antibiotics authorised for medication of dogs have a high degree of completeness. In 2014, the overall consumption of products for oral medication of dogs was 881 kg compared to 1 348 kg in 2010. Aminopenicillins, first generation cephalosporins and lincosamides were by far the classes with largest consumption in 2014 (300, 278 and 151 kg, respectively).
Figure 1.29. Consumption of the five largest antibiotic classes among antibiotics for oral medication of dogs expressed as packages per 1000 dogs. Data include antibiotics authorised for veterinary use as well as antibiotics for human use. 160 140 Packages per 1000 dogs
42
120 100 80 60 40 20 0
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Aminopenicillins
Aminopenicillins & inhibitor
Cefalosporins 1st gen.
Macrolides & lincosamides
Fluoroquinolones
In 2006, the total consumption of antibiotics for oral use in dogs, both veterinary antibiotics and those authorised for use in humans, corresponded to 563 packages per 1000 dogs. Since then, the consumption has decreased to 282 packages per 1000 dogs (-50%). Trends over time for the five largest classes (90% of the total sales) are illustrated in Figure 1.29. The most prominent changes relative to 2006 are noted for cephalosporins (-79%), fluoroquinolones (-73%) and amino penicillins with clavulanic acid (-60%). As described in Svarm 2008, the emergence of infections with multiresistant methicillin-resistant Staphylococcus pseudintermedius and methicillin-resistant S. aureus triggered a number of national and local initiatives. This has most likely led to changes in prescribers’ behaviour, which in turn explains the downward trends in sales of antibiotics for dogs.
Comparison of antibiotic consumption in human and veterinary medicine Data included and calculations The figures on total amount of antibiotics consumed for systemic use of antibiotics to humans (ATC group J01 excluding methenamine and JA07AA oral glycopeptides; out-patient and hospital sales) were retrieved as defined daily doses and calculated to kg active substance. Figures on sales of antibiotics for use in animals (QJ01 and QJA07AA, total sales) are those presented in “Consumption of antibiotics for animals”. Sales for aquaculture were not included, nor were sales of drugs authorized for human use but sold for animals. The contribution of such sales to the total volumes is minor. It was assumed that the amounts sold were also used. To estimate the biomass of the human population, data on population numbers by age were multiplied with the corresponding average body weights from studies made by Statistics Sweden. For animal body mass, the method for calculation of population correction unit was used (EMA 2011). This unit roughly corresponds to the total biomass of major animal populations, excluding dogs and cats.
Comparison of consumption in tonnes active substance In 2014, a total of 60.5 and 10.2 tonnes of antibiotics in included ATC classes were consumed in human and veterinary medicine, respectively. It should be noted that there is a lack of completeness of 5-10% of the sales of antibiotics for animals (See Completeness of data in Consumption of antibiotics for animals). Figure 1.30 displays the consumption of beta-lactam antibiotics. These substances are by far the most used antibiotics in both human and veterinary medicine and also represent the largest amounts measured as kilograms. Penicillins ((Q)J01C) represent most of the amount in kg active substance of antibiotics for both humans and animals; 76 and 60% respectively. The substances shown in
SWEDRES | SVARM 2014
Figure 1.31 are consumed in smaller quantities (n.b. the difference in indexation of the x-axis between the figures), but given their chemical and pharmacological properties, their impact on the emergence of antibiotic resistance and the environment is probably more pronounced than that of the penicillins. In the figures, only antibiotics consumed in a total quantity exceeding 1 000 kg during 2014 are included. The only class where use in animals outweighs human consumption is trimethoprim-sulphonamides, of which two thirds are sold for horses. Figure 1.30. Consumption of beta-lactam antibiotics in human and veterinary medicine, kg active substance, 2014. Please note the difference in indexation of the x-axis between figures 1.30 and 1.31.
Aminopenicillins (Q)J01CA, (Q)J01CCR
Penicillin V and G (Q)J01CE incl.- (Q)J01RA
Beta-lactamase resistant penicillins-(Q)J01CF
Comparison of consumption expressed as mg per estimated kg biomass In 2014, the sales were 96.4 and 12.7 mg active substance per estimated kg biomass in human and veterinary medicine, respectively. In Figure 1.32 a comparison of consumption of antibiotics for use in humans and animals are shown expressed as mg per estimated kg biomass. Only classes where the total consumption exceeded 1000 kg active substance are shown. Data on the total consumption does not take the heterogeneity of the likelihood of exposure within the population into account. This is especially true for data on consumption for use in animals, as certain substances may only or mainly be sold for use in one particular animal species. This means that the selective pressure in a particular subset of the population (i.e. a particular animal species) can be far larger than in the total population. Nevertheless, in Figure 1.32 the largest difference is noted for the fluoroquinolones where consumption in humans is 83 times higher than in animals. Figure 1.32. Consumption of antibiotics in humans and animals expressed as mg active substance per estimated kg biomass in 2014.
25 20 15 10
Humans
Macrolides & lincosamides (Q)J01FA, (Q) J01FF Trimethoprim & sulphonamides - (Q)J01EA, (Q)J01E Fluoroquinolones (Q)J01MA 0
500
1000 1500 2000 2500 3000 3500 4000 kg active substance
Veterinary medicine
Human medicine
Animals
er th O
G d
en
an
op in
llin ci
Pe
ni
Te t Tetracyclines - (Q)J01AA
re Be ic illi si ta st -l ns an ac t p ta Ce en ma ic se ph i ca alo llins rb sp ap or Tr ene ins su ime ms & lp th ho op na rim M mid & lin acr es co oli sa de Fl m s uo id & ro qu es in ol on es
5
ra
Figure 1.31. Consumption of fluoroquinolones, macrolides, lincosamides, trimethoprim and suphonamides, and tetracyclines in human and veterinary medicine, kg active substance, 2014. Please note the difference in indexation of the x-axis between Figure 1.30 and 1.31.
30
Am
Human medicine
35
es
30000
V
Veterinary medicine
25000
in
10000 15000 20000 kg active substance
cl
5000
40
cy
0
mg/kg estimated biomass
45 Cephalosporins and carbapenems - (Q)J01D
43
44
SWEDRES | SVARM 2014
SWEDRES | SVARM 2014
Antibiotic resistance Notifiable diseases For humans four bacterial types of antibiotic resistance are included in the Swedish Communicable Diseases Act. These are Staphylococcus aureus with resistance to methicillin and other betalactam antibiotics (MRSA), Streptococcus pneumoniae with reduced susceptibility or resistance to penicillin (PNSP), Enterococcus faecalis and Enterococcus faecium with resistance to vancomycin (VRE), and Enterobacteriaceae carrying ESBL or ESBLCARBA. As in previous years, the reports of ESBLs have outnumbered the other three types manifold. In animals, all methicillin-resistant coagulase-positive staphylococci are notifiable, thus including MRSA and Staphylococcus pseudintermedius (MRSP). Also notifiable in animals is ESBLCARBA-producing Enterobacteriaceae. In the monitoring, specific attention is also paid to the occurrence of other ESBL-producing Enterobacteriaceae and VRE.
Overview of sampling and culture results in humans Denominator data has been collected since 2001 on a voluntary basis from the microbiology laboratories in Sweden and reported each year in Swedres-Svarm as background data.
The reporting laboratories, this year 24 out of 25, cover more than 95% of the population. Some modifications of the data collection has been made during the years, for instance were analyses of toxinpositive C.difficile included year 2008, urine cultures analyses included year 2009 and positive blood culture analyses included year 2010. Complete data for 2014 are given in the section Demographics and denominator data. In the following figures the annual numbers of requested analyses per 100 000 inhabitants are presented for: blood culture, MRB screening culture, general culture, throat culture, nasopharynx culture, urine culture, and C. difficile. Number of positive blood cultures per 100 000 inhabitants and number of isolated S. aureus, E. coli, S. pneumoniae, and S. pyogenes in all specimen types per 100 000 inhabitants are also given. In the last eight years the number of blood cultures, and MRB screening cultures requested annually per 100 000 inhabitants increased. The trends for number of positive blood cultures, and isolated E. coli and S. aureus, regardless of specimen type, were also increasing. Throat cultures and the isolation of S. pyogenes decreases, likely due to an increased use of near patient testing for streptococcal tonsillitis.
500
4000
400
3000
300
2000
200
1000
100
300
2500
250
2000
200
1500
150
1000
100
500 0
50 2007 2008 2009
2010 2011 2012 2013
2014
0
Blood cultures
General culture
Staphylococcus aureus
Escherichia coli
Screen MRB
Positive blood cultures
Streptococcus pneumoniae
Streptococcus pyogenes
12000
1600
10000
1400 1200
8000
1000
6000
800 600
4000
400
2000
200 2007 2008 2009 2010 2011 2012 2013 2014 Nasopharynx
Throat
Urine
0
Number of faeces analyses per 100 000 inhabitants
1800
0
0
2007 2008 2009 2010 2011 2012 2013 2014
350
3000
900
140
800
120
700
100
600 500
80
400
60
300
40
200
20
100 0
2008
2009
2010
Faeces- C. difficile (toxin)
2011
2012
2013
2014
0
Number of positive streptococcus cultures per 100 000 inhabitants
5000
0
Number of nasopharynx and throat analyses per 100 000 inhabitants
600
3500
Number of toxinpositive C. difficile samples per 100 000 inhabitants
700
Number of positive S. aureus and E. coli cultures per 100 000 inhabitants
800
6000
Number of positive blood cultures per 100 000 inhabitants
7000
Number of urine analyses per 100 000 inhabitants
Number of analyses per 100 000 inhabitants
FIGURE 2.1. Denominator data for humans. Number of requested analyses, and number of positive analyses or isolates. All per 100 000 inhabitants.
Toxinpositive Clostridium difficile
45
SWEDRES | SVARM 2014
ESBL-producing Enterobacteriaceae
Notifications of ESBL-producing bacteria according to the Communicable Disease Act
ESBL-producing Enterobacteriaceae in humans
A total of 8902 cases were notified in 2014, an increase with 9% compared to 2013. Since 2007 the number of cases has increased continuously each year with 9-33%. The national incidence was 91 cases per 100 000 inhabitants. An increased incidence was seen in 15 out of 21 Swedish counties, with the highest incidence found in Jönköping county (120 cases per 100 000 inhabitants; Figure 2.2). There was a 4-fold difference in incidence between the counties. In part the large variation in incidence between counties could be explained by different screening and contact tracing practices. The most commonly reported species was Escherichia coli found in 89% of all cases, followed by Klebsiella pneumoniae with 7% (Table 2.1). ESBL-producing Salmonella species and Shigella species were reported in 16 and 23 cases respectively in 2014. ESBL-producing bacteria were most often found in urine samples (59%). The second and third most common sources were fecal and rectal samples with 19% and 9% respectively. Fecal and rectal samples are usually screening samples and in recent years screening has increased. Isolates from blood and wound samples constituted 4% and 3%, respectively, and isolates were from other samples in 7% of the cases. Age, gender and sample type distribution are given in Figure 2.3. During 2014, 520 cases with ESBL-producing bacteria were reported as invasive infections (all in blood). This is an increase of 29% compared to 402 persons reported in 2013. Among these, 435 were new cases for 2014 and 85 were known carriers of ESBL, notified during the previous years. For details on the frequencies of antibiotic resistance among clinical samples, especially blood and urine samples, please see below in chapter: Resistance in clinical isolates from humans.
Background
ESBL-producing Enterobacteriaceae has been notifiable by clinical laboratories according to the Communicable Diseases Act since February 2007. As there is no clinical reporting, information on ESBL cases is limited to data on age, gender and sample type. From 2010, the definition of ESBL included not only classical ESBLs (=ESBLA), which are inhibited by clavulanic acid, but also plasmid-mediated AmpC-betalactamases (= ESBLM) and metallo-betalactamases / carbapenemases (= ESBLCARBA). In March 2012 the notifications of bacteria with ESBLCARBA were extended to include both a laboratory and a clinical report, additionally contact tracing became mandatory.
TABLE 2.1. Distribution of species among human cases of ESBLproducing Enterobacteriaceae 2014. Species
Number of cases
Proportion, %
8161
89.2
668
7.3
Proteus mirabilis
72
0.8
Citrobacter species
40
0.4
Shigella species
23
0.3
Salmonella species
16
0.2
166*
1.8
Escherichia coli Klebsiella pneumoniae
Enterobacteriaceae (not specified or species not reported) Total number reported
9146**
* Distinction between an ESBL and a chromosomally mediated AmpC was not made for these bacteria. **In 239 patients two or more ESBL-producing species were reported resulting in a higher number of isolates than number of cases reported.
FIGURE 2.2. The incidence (cases per 100 000 inhabitants) of ESBL-producing Enterobacteriaceae in Swedish counties 2010-2014, arranged according to incidence figures 2014.
140 120 100 80 60 40 20
2011
2012
2014
nd
n
ot
la
te G
ot rb
or
gö er
st Ö
N
an
d
tla nd
na
rrl
ar
no er st
Vä
nd la
al D
n
an m
Sö de r
nd tla
er Vä
2013
bo tte
ge
County 2010
st
la
in
m Jä
Bl
m
Vä r
ek
nd
o
g
re br
or
Ö
eb
la G
äv l
sa
nd
la
al H
l
ar lm
pp U
Ka
to ta n
ed e Sw
nd
Sk ån e
an m st
G ra st
Vä
Vä
öt
al
la
ol
an d
m
g er ob
kh oc St
on
nk
öp
in g
0
Kr
ESBL-cases per 100 000 inhabitants
160
Jö
46
SWEDRES | SVARM 2014
FIGURE 2.3. Age, gender and sample type distribution of human cases of ESBL-producing E. coli and K. pneumoniae 2014. K. pneumoniae, women
E. coli, women 50
350
40
Number of cases per 100 000 inhabitants
20
other
urine
wound
other
The incidence in age groups and gender differed between species (Figure 2.3). ESBL-producing E. coli were derived from women in 65% of the cases. They had a median age of 51 years compared to 62 years for men. The K. pneumoniae ESBL cases were more equally distributed between sexes, with median ages of 57 years for women and 64 years for men.
Enterobacteriaceae with carbapenemases (ESBLCARBA) From the 15th of March 2012 Enterobacteriaceae producing carbapenemases (ESBLCARBA) became notifiable for both physicians and laboratories. Before this date Enterobacteriaceae with an ESBLCARBA had been notified from the laboratories only and additional information about the cases had been gathered on a voluntary basis. The rationale behind the strengthened notification was that ESBLCARBA, pose an even greater threat because of the further limited treatment options. ESBLCARBA of clinical importance belong to one of three kinds, either KPC (K. pneumoniae Carbapenemase), MBLs (Metallo-betalactamases, i.e. NDM, VIM and IMP) or certain OXA-enzymes. In Sweden, all enzymes with carbapenemase activity are denoted ESBLCARBA (Giske et al., 2009). A total of 141 cases with ESBLCARBA have been reported in Sweden 2007-2014. In 2014, 46 new cases with an ESBLCARBA-producing Enterobacteriaceae were reported, compared to 39 new cases in 2013. Cases were reported from twelve Swedish counties with almost half of the cases being reported from Stockholm and Skåne. Fifteen cases were reported as domestic and thirty-one cases were acquired abroad. (Figures 2.4). The five most common countries for imported infections were India (5 cases), Spain (4), Egypt (3), Greece (2) and Iraq (2).
urine
>85
80-84
70-74
75-79
60-64
65-69
50-54
55-59
40-44
wound
>85
80-84
70-74
75-79
65-69
60-64
50-54
blood
55-59
40-44
fecal/rectal
45-49
20-24
10-14
>85
80-84
75-79
70-74
65-69
60-64
55-59
40-44
50-54
blood
other
A majority of the domestic cases, twelve cases, were detected by clinical symptoms, two were found by contact tracing and one was found by screening. Of the imported cases, twentythree were detected through targeted screening and seven due to clinical symptoms. The way of acquisition for the domestic cases were community acquired infections (2 cases), by household contacts (1 case), or related to hospital care (2 cases) or care outside hospital (1 case). For nine domestic cases there was no information of acquisition. Among the imported cases hospital acquired infection dominated (23 cases). The other ways of acquisition for the imported cases in 2014 were, community acquired infections (3 cases), infections related to healthcare/care outside hospital (2 cases), and for one case the infection was stated to be food-and waterborne related. For two of the imported cases there was no information of acquisition. FIGURE 2.4. Number of human cases of ESBLCARBA annually notified in Sweden 2007-2014. 50 45 40 Number of cases
fecal/rectal
45-49
30-34
35-39
25-29
20-24
10-14
15-19
0-4
urine
0
15-19
10
50 0
45-49
20
0-4
100
other
30
5-9
150
wound
40
Number of cases per 100 000 inhabitants
200
5-9
Number of cases per 100 000 inhabitants
250
blood
K. pneumoniae, men
50
300
30-34
fecal/rectal
E. coli, men 350
35-39
20-24
>85
80-84
70-74
75-79
60-64
wound
30-34
blood
65-69
50-54
55-59
40-44
45-49
30-34
35-39
20-24
fecal/rectal
0
35-39
urine
25-29
10-14
15-19
0-4
5-9
0
25-29
10
50
25-29
100
10-14
150
30
15-19
200
0-4
250
5-9
Number of cases per 100 000 inhabitants
300
35 30 25 20 15 10 5 0
2007
2008
2009
Domestic
2010
2011
Imported
2012
2013 No data
2014
47
48
SWEDRES | SVARM 2014
In focus
ESBL producing Escherichia coli – food as a potential dissemination route to humans This is a summary of a joint project 2009-2014 between Public Health Agency of Sweden, National Veterinary Institute and National Food Agency. The project was performed between 2009-2014 and financed by the Swedish Civil Contingencies Agency. In Sweden, ESBL producing Enterobacteriaceae, including Escherichia coli, is the most commonly reported resistance type, with 8 902 cases in 2014. The main aim of this study was to investigate food as a potential source and dissemination route for ESBL-producing E. coli to humans. A further aim was to examine how this type of resistance is distributed in humans, foods, farm animals and the environment. By investigating the prevalence and genetic similarities between ESBL-producing E. coli from the different categories, an indirect measure of dispersion between settings was obtained. Such information is important for future risk management of foodstuffs in relation to ESBL-producing E. coli. The study used analytical data on approximately 5 300 samples taken from foods (domestic and imported), farm animals, healthy volunteers, severely ill patients, the environment and sewage water. All samples were collected in Sweden. Except for the human clinical samples, the prevalence of ESBL-producing E. coli was determined by selective cultivation. To investigate similarities between ESBL-producing E. coli from different sample groups, molecular typing and antibiotic susceptibility testing followed by descriptive statistics were used. Escherichia coli producing ESBL were frequently found on chicken meat, regardless of country of origin.They also occurred to a lesser extent on imported foods: pork, beef, leafy vegetables and farmed fish foodstuffs. ESBL-producing E. coli
isolated from imported foods and foods from other EU countries differed from those isolated from foods, only chicken meat, produced in Sweden (Figure). In many countries, carriage of ESBL-producing bacteria is widespread and the results from this study confirm previous findings that travelling outside the Nordic countries increases the risk of becoming a carrier. The same types of ESBL-producing E. coli found in severely ill patients and community carriers were also found in the Swedish environment and sewage water (Figure). A limited number of the isolates of ESBL-producing E. coli found in imported foods (n=5) and farm animals (n=7) were of the same type (identical MLST, plasmid replicon type and gene encoding ESBL) as those found in severely ill patients (n=1) and healthy individuals (n=4). In conclusion, the study indicated that food on the Swedish market is a limited contributor to the occurence of ESBL-producing E. coli within the healthcare sector. When comparing the genes encoding ESBL there are three separate populations in Sweden today, one in Swedish foods and farm animals, one in imported foods, and one in humans and the environment. The results provide a picture of the current Swedish situation regarding occurrence of ESBL-producing E. coli. However, antibiotic resistance is dynamic. The national setting is influenced by changes in global epidemiology and the situation can change rapidly. Therefore, continuous monitoring of the prevalence of ESBL-producing bacteria in foods and in the environment, as well as in humans, is needed so that future risks can be assessed and management plans updated. Limiting the spread of resistance and maintaining the efficacy of antibiotics is a major challenge in the world today.
Figure. Distribution of ESBL-genes. 100% 90% 80%
Other genes bla-ctx-m-55
70%
bla-shv-12 60%
bla-ctx-m-3 bla-ctx-m-8
50%
bla-ctx-m-2 40%
bla-ctx-m-27 bla-ctx-m-14
30%
bla-ctx-m-1 20%
bla-cmy-2 bla-ctx-m-15
10% 0%
Imported foods (n=101)
Swedish foods (n=74)
Farm animals (n=53)
Community carriers (n=101)
Blood infections (n=379)
Environment (n=56)
Sewage water (n=55)
SWEDRES | SVARM 2014
FIGURE 2.5. Number of cases and types of ESBLCARBA in Enterobacteriaceae in Sweden 2009-2014. In samples from two persons in 2013, and in three persons 2014 two different enzyme types were detected in the same isolate, and in samples from five persons in 2013 and in six persons in 2014 the same enzyme type was detected in more than one bacterial species. 35 30
Number of cases
25 20 15 10
2009
2010
2011 NDM
2012
OXA-48
KPC
VIM
2013
Other spp
K. pneumoniae
E. coli
Other spp
K. pneumoniae
E. coli
Other spp
K. pneumoniae
E. coli
Other spp
K. pneumoniae
E. coli
Other spp
K. pneumoniae
Other spp
E. coli
K. pneumoniae
0
E. coli
5
2014
IMP
mation on way of acqusition. With the IMP-isolate five different types of ESBLCARBA have been identified so far. The enzyme types OXA-48 and NDM continues to dominate in 2014. Both these types of enzymes were detected in E. coli and K. pneumoniae isolates, in most cases together with CTX-M (=ESBLA) and/ or pAmpC CIT (=ESBLM) enzymes. In Figure 2.6 all ESBLCARBA enzymes isolated from cases notified in Sweden 2007-2014 are presented in relation to region of acquisition. All isolates with ESBLCARBA were multi resistant, leaving very few options for antibiotic treatment.
FIGURE 2.6. Carbapenemase subtypes isolated from human cases of ESBLCARBA notified in Sweden 2007-2014, presented in relation to region of acquisition. Unknown Africa Asia Europe Middle East North/South America
ESBL-producing Enterobacteriaceae in animals
Sweden
Farm animals 0
5
10
15
20
25
30
35
40
Number of cases NDM
OXA-48
KPC
VIM
IMP
The ESBLCARBA-producing Enterobacteriaceae were identified in fecal/rectal samples (20), urine (18), wound (5), respiratory samples (1), blood (1), and one biopsy sample. Two cases of invasive infection with ESBLCARBA were notified in 2014. For one of the invasive cases ESBLCARBA was first isolated from a wound sample. The cases were almost equally distributed between the sexes and the median ages were 64 and 58 years for women and men, respectively. In 2014 the most common carbapenemase-producing Enterobacteriaceae was K. pneumoniae (28 isolates) followed by E. coli (15 isolates). Genes coding for carbapenem resistance have also been detected in several other species of Enterobacteriaceae (Figure 2.5). In 2014 an isolate producing Imipenemase Metallo-beta-lactamase (IMP) was identified for the first time in Sweden. The IMP-producing carba penem-resistant Citrobacter species isolate was recovered from a urine sample from a domestic patient with no infor-
In Svarm, active screening for ESBL-producing E. coli (including plasmid-mediated AmpC) in healthy farm animals using samples collected at slaughter for the studies of indicator bacteria has been performed since 2008. During 2014, caecal samples from healthy broilers (n=200) and healthy turkeys (n=60) were screened for E. coli resistant to ESCs. Isolates with reduced susceptibility were further investigated by molecular methods for presence of transferrable genes coding for ESC resistance (for details see Material and methods, resistance in bacteria from animals). In Sweden, carbapenemase producing Enterobacteriaceae (ESBLCARBA) in animals are notifiable but this is not the case for classical ESBLs (ESBLA) or plasmid-mediated AmpC (ESBLM). The proportions of faecal samples positive for ESBLA or ESBLM in the most recent screenings of various animal species in Sweden are shown in Table 2.2. In 2014, ESBLA or ESBLM were detected in 71 (36%) of the caecal samples from broilers, but in none of the caecal samples from turkeys. One isolate from broilers carried the gene blaCTX-M-1 (i.e. ESBLA) and 70 isolates a gene of the CIT-group (i.e. ESBLM). The gene belonging to the CIT-group in those isolates has not been sequenced, but historically such isolates
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50
SWEDRES | SVARM 2014
have always carried the gene blaCMY-2. This has also been the dominating gene among broilers in Sweden since the high occurrence was discovered in 2010. The majority (68%) of the ESBLA or ESBLM from broilers was only resistant to betalactams. Other existing resistance traits were resistance to sulphonamides (19%), tetracycline
(10%), ciprofloxacin (10%) and nalidixic acid (7%). Seven isolates (10%) were multiresistant and all of these had, in addition to resistance to betalactams, resistance to sulphonamide and tetracycline in their phenotype. Among the 71 isolates with ESBLA or ESBLM from broilers, there were 8 that had decreased susceptibility to ertapenem
TABLE 2.2. Results of the most recent screening studies for E. coli with ESBLA or ESBLM in healthy individuals of different animal species. Animal species Year
Broilers
Calves
Dogs
Horses
Laying hens
Pigs
Turkeys
2014
2013
2012
2010
2012
2011
2014
Number of samples
200
202
84
431
69
184
60
Percent (%) ESBLA
<1
<1
0
1
4
2
0
Percent (%) ESBLM
35
0
1
0
9
0
0
TABLE 2.3. Clinical isolates of different bacterial species of Enterobacteriaceae, producing ESBLA or ESBLM enzymes, from companion animals and horses submitted 2008-2014. Animal species
Cats
Dogs
Horses
a
ESBLA or ESBLM
Bacterial species
CTX-M-14
Kluyvera spp.
CTX-M-15
Escherichia coli
CTX-M-15
Klebsiella pneumoniae
CMY-2
Escherichia coli
2008
2009
2010
2011
2012
2013
2014
1 1 1
1a
1
1
CMY-16
Escherichia coli
unknown
Escherichia coli
1
CTX-M-1
Enterobacter cloacae
CTX-M-1
Escherichia coli
CTX-M-2
Escherichia coli
CTX-M-3
Enterobacter spp.
CTX-M-3
Escherichia coli
CTX-M-9
Escherichia coli
CTX-M-15
Enterobacter spp.
CTX-M-15
Escherichia coli
CTX-M-15
Klebsiella pneumoniae
CTX-M-27
Escherichia coli
SHV-12
Escherichia coli
CMY-2
Escherichia coli
CMY-2
Proteus mirabillis
unknown
Escherichia coli
CTX-M-1
Enterobacter spp.
CTX-M-1
Escherichia coli
CTX-M-1
Klebsiella oxytoca
CTX-M-1
Serratia odorifera
CTX-M-9
Escherichia coli
CTX-M-14
Escherichia coli
CTX-M-15
Escherichia coli
1
CTX-M-15
Klebsiella pneumoniae
1
SHV-12
Citrobacter braakii
SHV-12
Enterobacter amnigenus
SHV-12
Enterobacter cloacae
SHV-12
Enterobacter spp.
SHV-12
Escherichia coli
SHV-12
Escherichia hermanii
SHV-12
Klebsiella oxytoca
SHV-12
Klebsiella pneumoniae
unknown
Enterobacter cloacae
unknown
Escherichia coli
1
unknown
Klebsiella pneumoniae
5
1 4 1
1
1
3
1 1 2 1
2
1
1
2
1
1
2
1
2
3
2
6
1 3
1
1 2
1
9
4
5
5
1 1
1
2
9
1 8
3
3
2 1
1 1 1 1 1 1 1 1 2
3
5
2
2
3
3
1 2 1 1
The gene belongs to the CIT-group, but it has not been sequenced and it is therefore uncertain if the enzyme is CMY-2.
SWEDRES | SVARM 2014
FIGURE 2.7. Proportion (%) of samples from broilers positive for ESBLA or ESBLM from 2010 to 2014. 60 50 40 30 20 10 0 2010
2011
2012
2013
2014
Proportion (%) of samples with ESBL without using enrichment, 2014
Proportion (%) of samples with ESBL
(MIC 0.12 – 0.25 mg/L), but no isolates with decreased susceptible to imipenem or meropenem. Two of the isolates with decreased susceptibility to ertapenem, including the one with MIC of 0.25, were further investigated with PCR but no genes conferring resistance to carbapenems were detected. Ertapenem is known to have lower specificity to detect carba penemase producing Enterobacteriaceae than imipenem and meropenem (Cohen Stuart et al., 2010). Since 2011, there has been a gradual decrease in the proportion of samples from broilers that are positive for ESBLA
or ESBLM (Figure 2.7), and the difference between the occurrence in 2012 and in 2014 is statistically significant (p<0.01, X2). Furthermore, in 2014 the screening method was altered compared to 2013 and pre-enrichment in MacConkey broth with cefotaxime was included before the samples were cultured on MacConkey agar with cefotaxime (for details on methodology see Material and methods, resistance in bacteria from animals). The samples were also cultured in duplicate according to the previous method and if only that had been used, ESBLA or ESBLM would have been isolated from 52 (26%) of the samples. When that figure is compared to figures from 2013, the difference is significant (p=0.01, X2). The occurrence of ESBLA or ESBLM in turkeys has been investigated in two consecutive years, 2013 and 2014, and a total of 115 samples have been analysed. No such resistance has been found even though 28 (24%) isolates have shown phenotypical ESC resistance. Furthermore, in 2014 phenotypical resistance to ESC was detected in one isolate of indicator E. coli from a turkey, but genes conferring transmissible ESBLA or ESBLM resistance were not detected. Companion animals and horses
During 2014, a total of 30 isolates of Enterobacteriaceae with phenotypic resistance to ESCs were confirmed to produce ESBLA or ESBLM at SVA (Table 2.3). The isolates were from cat (n=1), dogs (n=21) and horses (n=8), and the majority was isolated from wounds or from the urogenital tract.
TABLE 2.4. Notifications of human cases of MRSA according to the Communicable Disease Act 2010-2014 by county. County
2010
2011
2012
2013
2014
No
Inc *
No
Inc*
No
Inc*
No
Inc*
No
Inc*
Blekinge
8
5.2
17
11.1
24
15.8
32
20.9
37
24.0
Dalarna
27
9.7
38
13.7
33
11.9
35
12.6
61
21.9
Gotland
5
8.7
9
15.7
11
19.2
15
26.2
17
29.7
Gävleborg
26
9.4
36
13.0
35
12.7
51
18.3
50
17.9
Halland
40
13.4
51
16.9
47
15.5
58
18.9
55
17.7
Jämtland
28
22.1
19
15.0
33
26.1
54
42.7
51
40.2
Jönköping
54
16.0
61
18.1
82
24.2
126
36.9
118
34.3
Kalmar
72
30.8
45
19.3
72
30.8
82
35.1
140
59.4
Kronoberg
23
12.5
40
21.7
40
21.5
54
28.9
89
47.1
Norrbotten
21
8.4
20
8.0
31
12.5
39
15.6
73
29.2
Skåne
313
25.2
369
29.5
384
30.4
394
30.9
488
37.9
Stockholm
412
20.0
502
24.0
589
27.7
623
28.8
685
31.2
Södermanland
30
11.1
34
12.5
32
11.6
50
18.0
66
23.5
Uppsala
41
12.2
42
12.4
80
23.4
76
22.0
98
28.1
Värmland
28
10.2
48
17.6
40
14.6
80
29.2
66
24.0
Västerbotten
39
15.0
20
8.0
21
8.1
34
13.0
40
15.2
Västernorrland
30
12.4
24
9.9
35
14.5
40
16.5
56
23.0
Västmanland Västra Götaland Örebro Östergötland Total
32
12.7
28
11.0
31
12.1
50
19.3
68
26.0
264
16.7
347
21.8
360
22.5
439
27.2
463
28.4
40
14.3
44
15.6
55
19.4
50
17.5
106
36.8
47
10.9
71
16.5
62
14.3
72
16.4
94
21.3
1580
16.8
1884
19.9
2097
21.9
2454
25.4
2921
30.0
*=Incidence (cases per 100 000 inhabitants)
51
SWEDRES | SVARM 2014
Zoonotic aspects on ESBL-producing Enterobacteriaceae In 2011, the European Food Safety Authority (EFSA) concluded that there was indirect evidence for transmission of Enterobacteriaceae with ESBLA or ESBLM, and their corresponding genes, between farm animals and humans, most likely through contaminated food (EFSA, 2011). The possibility for direct transfer to people handling animals should also be kept in mind. Both of these aspects has also been investigated in a recent publication by deBeen et al. (2014). The available data show that ESBL-producing bacteria are rare in animals in Sweden with the exception of poultry where E. coli with ESBLM resistance is found in a large proportion of birds. The majority of isolates from humans in Sweden is of the ESBLA type and only 6% are of the ESBLM type. Furthermore, a recent Swedish study investigating the potential overlap between clinical human isolates and isolates from healthy farm animals and food concluded that the overlap was limited and that food in Sweden was not a source for ESBLs for humans (see In focus ESBL producing Escherichia coli – food as a potential dissemination route to humans for more details). Nevertheless, continued vigilance towards development of reservoirs of ESBL-producing Enterobacteriaceae in animals is warranted.
Methicillin-resistant Staphylococcus aureus (MRSA) MRSA in humans Background
MRSA has been mandatory notifiable since the year 2000. Infection control programmes have been developed and implemented locally under supervision of the County Medical Officers (CMO) and infection control teams. These programmes are based on early case-finding through extensive screening of patients with risk factors and contact tracing combined with infection control measures such as isolation of MRSA positive cases and intensive campaigns on basic hygiene precautions. The notifications have been reviewed and complemented with available relevant epidemiologic information from investigations around each case in collaboration with the CMOs. This has been performed the last eight years. Notifications of MRSA according to the Communicable Disease Act
In 2014 a total of 2921 cases of MRSA were notified, an increase by 467 cases (19%) compared to 2013 (Figure 2.8). The average national incidence was 30 cases per 100 000 inhabitants with higher than average incidence figures in Kalmar (59.4), Kronoberg (47.1), Jämtland (40.2), Skåne (37.9), Örebro (36.8), Jönköping (34.3) and Stockholm (31.2) counties. In 2014, 50% (n=1452) of all reported MRSA were domestic cases and 49% (n=1428) were acquired abroad. Syria (183 cases), Iraq (97), Philippines (76), Eritrea (64) and Egypt (44) made up the five most common countries for imported MRSA. For approximately one percent country of infection was missing (“No data”). Among the domestic MRSA cases 2014, the incidence was highest in the age group 0-6 years, followed by the age group 80 years and older (Figure 2.9). The incidence of MRSA among the very old and the very young was substantially
FIGURE 2.8. Number of human cases of MRSA notified annually by country of infection, Sweden 2010-2014. 3500 3000 Number of cases
52
2500 2000 1500 1000 500 0
2010
2011
2012
2013
Domestic
Imported
No data
2014
higher (≥ 23) than in the other age groups. In the other age groups the incidence remained at a low but slightly increasing level, in 2014 reaching 10-14. Among children (0-6 years), the infants (0 years) had by far the highest incidence (Figure 2.10). Infant MRSA cases were mainly detected through contact tracing (56%), 24% by screening and 19% by clinical symptoms. Of 160 cases among infants, 29 (18%) were hospital related, 18 of these were part of neonatal outbreaks comprising three or more cases, 116 cases (72%) were community acquired. In 2014, 43% of the domestic cases were identified through contact tracing, 10% in targeted screening, and 45% during investigations of clinical symptoms (Figure 2.11 A). For imported cases the corresponding figures were 17%, 48%, and 33%, respectively (Figure 2.11 B). The majority of samples from investigations of clinical symptoms were wound samples (62%). Invasive MRSA infection was reported in 39 cases 2014 compared to 42 cases 2013. Thirty of those were newly notified cases 2014 and nine occurred in patients already known to carry MRSA in previous years. Epidemiological classification of the acquisition of MRSA was based on information in the clinical notifications and from subsequent investigations by the CMOs, Figures 2.11, A and B. Community-acquired infections dominated among domestic cases 2014 and comprised 76% (n=1100) of all domestic cases, Figure 2.12 A. Among the imported cases the proportion of community acquired infections was 50% (n=707), Figure 2.12 B. Hospital acquired MRSA was comparatively more common in imported cases, 28% (n=393), than among domestic cases, 8% (n=109). The number of domestic cases with hospital acquired MRSA decreased from 147 (2013) to 109 (2014). On the other hand, the number of domestic cases with MRSA acquired in healthcare/care outside hospital increased slightly to 112 in 2014 compared to 91 in 2013. In addition, the number of imported cases with MRSA acquired in healthcare/care outside hospital increased to 113 (8%), from 65 (6%) in 2013. Outbreak investigations
During 2014, twenty outbreaks (three or more cases/outbreak) were reported in nine different counties. These outbreaks comprised 100 cases, representing 3% of all cases of
SWEDRES | SVARM 2014
FIGURE 2.9. Incidence per age group of all notified domestic human cases of MRSA in Sweden 2010-2014.
Cases per 100 000 inhabitants
Cases per 100 000 inhabitants
45 40 35 30 25 20 15 10 5 0
FIGURE 2.10. Incidence of notified domestic human cases of MRSA in the age group 0-6 years in Sweden 2010-2014.
2010
2011 0-6
2012
7-19
20-59
2013 60-79
160 140 120 100
2014
80%
80% 80%
60%
60% 60%
40%
40% 40%
20%
20% 20%
2012 (1078) Domestic
Clinical symptoms Contact tracing
2013 (1266)
2014 (1452)
0% 0%
100% 100%
80%
80% 80%
60%
60% 60%
40%
40% 40%
20%
20% 20%
2010 (721)
2011 (879)
2012 (998) Imported
Clinical symptoms Contact tracing
2013 (1157)
0
2010
2011 1y
2010 2010 (834) (834)
2011 2011 (973) (973)
Community-acquired Community-acquired Hospital-acquired Hospital-acquired
Screening Other/missing
100%
0%
20
2014 (1428)
Screening Other/missing
MRSA in 2014. The three most common spa-types were t790, t002 and t2958. Fourteen outbreaks were reported from healthcare institutions outside hospitals, whereas four were hospital outbreaks. One of the outbreaks in 2014 was connected to sport. Epidemiological typing of MRSA
The primary method used for epidemiological typing of MRSA isolates sent to the Public Health Agency of Sweden is spa-typing. This is a DNA sequence based method with a standardized, unambiguous and internationally well recognized nomenclature (http://spaserver.ridom.de/). In addition,
2012 2y
3y
2013 4y
2014 5y
6y
FIGURE 2.12, A and B. Epidemiological classification of human cases of MRSA, A, top: domestic, and B, bottom: imported , Sweden 20102014. Number of reported cases each year is shown in brackets. 100% 100%
2011 (973)
40
0y
100%
2010 (835)
60
80-
FIGURE 2.11, A and B. Indications for sampling of domestic (A, top) and imported (B, bottom) MRSA cases in Sweden 2010-2014. Number of reported human cases each year is shown in brackets.
0%
80
0% 0%
2010 2010 (731) (731)
2011 2011 (879) (879)
Community-acquired Community-acquired Hospital-acquired Hospital-acquired
2012 2013 2014 2012 2013 2014 (1078) (1266) (1452) (1078) (1266) (1452) Domestic Domestic Healthcare/Care outside hospital Healthcare/Care outside hospital Other/missing Other/missing
2012 2013 2014 2012 2013 2014 (998) (1157) (1428) (998) (1157) (1428) Imported Imported Healthcare/Care outside hospital Healthcare/Care outside hospital Other/missing Other/missing
PVL status (absence/presence of genes coding for PVL) of each isolate is determined and used as an epidemiological marker that differentiates MRSA variants within spa-types. In 2014, spa-typing results were available for MRSA isolates from 98% of the notified cases. All but 13 of the 2856 isolates were typable, and a total of 402 spa-types were recorded. The ten most common spa-types in 2010-2014 are listed in Table 2.5. In 2014, 46% of the cases (n=1322) had an MRSA with a top ten spa-type. Seven of these spa-types have been among the top ten during 2010-2014; t223, t008, t044, t002, t127, t019 and t437. Three of the top ten spa-types in 2010, t032, t015 and t021, were not seen among the top ten
53
54
SWEDRES | SVARM 2014
TABLE 2.5. The ten most common spa-types among MRSA from notified human cases in 2010 - 2014. Number of notifications per spa-type and percent PVL-positive isolates are shown for 2013 and 2014. 2010 spa-type
2011 spa-type
2012 spa-type
t008
t008
t002
t008
t002
t002
t008
t002
spa-type
2013 No.
2014 No.
PVL-pos (%)
spa-type
176
88
t223
232
3
166
29
t008
186
81
PVL-pos (%)
t044
t019
t019
t223
139
1
t044
178
94
t019
t044
t223
t044
121
93
t002
172
32
t223
t223
t044
t127
104
27
t127
127
38
t437
t127
t127
t019
93
94
t304
120
10
t127
t437
t437
t304
59
8
t019
116
91
t032
t690
t015
t437
47
77
t690
71
72
t015
t015
t304
t690
46
46
t437
69
62
t021
t790
t690
t386
32
0
t386
51
6
t688
32
0
in 2014, and three of the top ten spa-types in 2014, t304, t690 and t386, were not seen among the top ten in 2010. Table 2.6 shows the top ten spa-types seen among isolates from cases with domestically acquired MRSA (n=680) and MRSA acquired abroad (imported, n=633), respectively, for 2014. Eight of the spa-types were present among the top ten in both groups; t002, t223, t008, t044, t127, t304, t019 and t690. The two spa-types seen only among the top ten in the domestic group were t267 and t790, and the two seen only among the top ten in the imported group were t437 and t386. In 2014, 35% of the cases (n=1011) had PVL-positive MRSA, compared to 37% in 2013. The most common MRSA variants seen during 2014 were t223, PVL-negative (n=225), t044, PVL-positive (n=167), t008, PVL-positive (n=151), t002, PVL-negative (n=117), t304, PVL-negative (n=108), t019, PVL-positive (n=106), t127, PVL-negative (n=79), t002, PVL-positive (n=55), t690, PVL-positive (n=51), t386 PVL-negative (n=48) and t688, PVL-negative (n=48).
TABLE 2.6. The ten most common spa-types among MRSA from notified human cases with domestically acquired MRSA and MRSA acquired abroad (imported), respectively, for 2014. Number of notifications per spa-type and percent PVL-positive isolates are shown.
spa-type
Domestic No. PVL-pos (%)
spa-type
Imported No. PVL-pos (%)
t223
109
5
t223
118
2
t002
106
32
t008
86
80
t008
100
82
t044
79
90
t044
96
97
t019
71
90
t304
64
8
t127
65
43
t127
59
34
t002
64
31
t019
44
95
t304
52
10
t690
38
87
t437
36
61
t267
32
0
t386
32
6
t790
32
0
t690
30
50
MRSA in animals In Sweden, MRSA in animals was first verified in 2006 and was made notifiable in 2008. During 2014, 18 new cases of MRSA were detected; 9 horses, 3 dogs, 3 hedgehogs, 2 cats and 1 dairy cow. Up to and including 2014, a total of 80 cases in animals have been confirmed (Tables 2.7 and 2.8). Most cases were detected in passive monitoring when animals with clinical infections were sampled. From such samples, isolates of S. aureus with resistance to oxacillin or cefoxitin were further analysed with confirmatory tests. Screening studies for active monitoring have been performed in pigs, cattle, horses and dogs during different years (see below). Farm animals
During 2014, a screening study in nucleus and multiplying pig herds was performed (see In focus: MRSA in pigs in Sweden). MRSA was not detected. Screening studies have previously been performed four times in pigs since 2006, with only one positive sample from pigs at slaughter in 2010. In dairy cattle, active monitoring of selected isolates of betalactamase producing S. aureus from milk samples has been ongoing since 2010, and 702 isolates have been tested up to and including 2014. One isolate from each submission of beta-lactamase producing S. aureus, if present, is tested. In this monitoring, PVL-negative MRSA with mecC was detected four times in 2010-2011 (Unnerstad et al., 2013), and once in 2013. PVL-positive MRSA with mecA was detected in 2012 and PVL-negative MRSA with mecA in 2014. During 2013, 513 isolates without beta-lactamase production were part of the monitoring as well, without any findings of MRSA. The above mentioned monitoring is performed on isolates with anonymized origin. In addition, PVL-positive MRSA with mecA was isolated from milk and body samples of cattle on the same dairy farm in 2012, 2013 and 2014 (see Zoonotic aspects on MRSA).
SWEDRES | SVARM 2014
Companion animals and horses
In dogs, cats and horses, there was no active monitoring of MRSA during 2014. A screening in dogs was performed in 2012 without detection of MRSA. Screening studies in horses have been performed twice, in 2007 and 2010, with only one positive sample in 2007. In 2014, MRSA was detected in clinical samples, mostly from wound infections, from three dogs, two cats and nine horses. Since the first finding of MRSA in companion animals, spa-type t032 has been most common (Table 2.8), and in isolates from horses spa-type t011, CC398, has dominated. Most isolates from horses have been from clinical cases with postoperative wound infections (Table 2.7), and all isolates from both companion animals and horses have been PVLnegative. Wild animals
In 2012, two MRSA-isolates were confirmed retrospectively from hedgehogs sent in for post mortem investigation in 2003 and 2011. In 2014, MRSA was isolated from three more hedgehogs. Two isolates came from post mortem investigations and one from a live animal with skin wounds. All isolates from hedgehogs were MRSA with mecC (Table 2.7). The isolate from 2003 was retrospectively found to be the first known isolate of MRSA from animals in Sweden, although not confirmed until 2012.
Zoonotic aspects on MRSA Zoonotic transmission of MRSA occurs by direct or indirect contacts, making farmers, animal caretakers, veterinarians and other persons in close contact with animals the population at risk. MRSA is reported globally in farm animals, companion animals and horses. During the last ten years, the zoonotic aspects on MRSA in farm animals, mostly in pigs but also in veal calves, broilers and dairy cows, has widened due to spread of livestock-associated MRSA CC398 in many countries. So far, there is no indication of zoonotic transmission of MRSA of importance in Sweden. However, sporadic transmission from humans to animals probably occurs, in particular concerning companion animals. MRSA CC398
Internationally, livestock-associated MRSA CC398 dominates in farm animals and can be of importance for the overall human MRSA burden in countries with low prevalence of MRSA in humans (EFSA, 2009). In countries with high prevalence of MRSA CC398 in pigs, the pig population constitutes a reservoir of MRSA with continuous transmission to people in close contact with pigs. In the screening study in 2014, MRSA was not detected in Swedish pigs, indicating a favourable situation, see In Focus: MRSA in pigs in Sweden. In Sweden, MRSA CC398 occurs among horses with spatype t011 as the most common type (Table 2.7). In humans, PVL-negative MRSA of five CC398-associated spa-types (t034, t011, t571, t108 and t1606) were detected
in 70 human cases in 2006-2014. The two dominating spatypes were t011 (n=34) and t034 (n=30). Twenty-one of the 70 cases were from 2014, fifteen with spa-type t011, five with t034 and one with t1606. Spa-type t011 was seen in both humans and horses. There is, however, no known indication of transmission between animals and humans, but the epidemiological information on these cases is scarce. MRSA with mecC
Isolates of MRSA with mecC were first reported internationally from dairy cows and humans in 2011 (García-Álvarez et al., 2011, Shore et al., 2011, Ito et al., 2012). In Sweden, MRSA with mecC has been isolated from milk from dairy cows, from hedgehogs and from cats (Table 2.7 and 2.8). MRSA with mecC has been found in 64 human cases 20112014. In total, 15 spa-types were seen among human isolates. The two most common were t373 (16 cases) and t843 (16 cases). Five spa-types have been seen among isolates from both humans and animals, t843 (dairy cows and hedgehog), t978 (hedgehog, cats), t3391 (hedgehog), t5771 (hedgehog) and t9111 (dairy cows). No epidemiological link is, however, known between the animal and human cases. Potential transmission from humans to animals
Staphylococcus aureus is a common cause of mastitis in dairy cows and the udder may constitute a reservoir. For example during milking, close contact between farmer and dairy cows may give good opportunities for transmission from human to cow, or vice versa. In 2012, PVL-positive MRSA of spa-type t002 was isolated from a dairy farmer and from several of the dairy cows and a few other cattle in the farm. Since MRSA of this spatype is common among humans in Sweden, it is likely that transmission has occurred from the farmer to cows. Hygienic measures were implemented on the farm in order to reduce the risk of transmission and several of the MRSA-positive cows were culled. This reduced the number of colonized or infected animals, but MRSA was still detected in cattle on the farm both in 2013 and 2014. In 2014, MRSA of spa-type t127 was detected in a milk sample with anonymized origin. Because this spa-type is common in humans, transmission from humans to cow can be suspected. There is, however, no epidemiological information available about this case. MRSA isolated from dogs and cats often belong to spatypes seen in MRSA from humans. This supports the view that humans often constitute the source of MRSA in companion animals (EFSA, 2009, CVMP, 2009). Once a carrier, an animal can act as a source of MRSA for other humans. The most common spa-type among Swedish dogs and cats has been t032. This type was one of the ten most common spa-types among human MRSA isolates in Sweden up to 2011, but in 2014 it was only found in 27 isolates. In later years, isolates with other spa-types have been detected in dogs, some of these types being common in humans.
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SWEDRES | SVARM 2014
TABLE 2.7. Large animals and wildlife. Isolates of methicillin-resistant Staphylococcus aureus (MRSA) in Swedish horses, pigs, cows and hedgehogs up to and including 2014. All isolates were positive for the mecA or mecC and nuc genes by molecular methods. Shaded areas indicate MIC above EUCAST cut-off values. Animal species
Year Clinical background/ Sampling site
Oxa
Horse
2007 screening
Horse
2008 post-op wound
Horse
2008 post-op wound
Horse Horse
Gen
Kan
Cip
Tmp
Chl
spatype
mecgene
0.5
>64
>32
1
>32
8
t011
mecA
0.5
64
>32
1
>32
8
t011
mecA
1
>64
>32
1
>32
8
t011
mecA
32
0.5
>64
>32
0.5
>32
8
t011
mecA
32
0.25
>64
>32
0.5
>32
8
t011
mecA
1
32
0.5
64
>32
0.5
>32
8
t011
mecA
≤0.25
1
64
1
>64
>32
1
>32
16
t011
mecA
≤0.25
≤0.25
32
0.12
4
32
0.25
>32
4
t011
mecA
>8
≤0.25
0.5
64
0.25
16
>32
0.25
>32
8
t011
mecA
4
1
≤0.25
0.5
32
0.25
64
>32
1
>32
8
t011
mecA
>4
8
0.5
2
64
1
>64
>32
1
>32
16
t011
mecA
>4
4
≤0.25
1
32
0.5
>64
>32
0.5
>32
8
t064
mecA
>16
>4
8
≤0.25
0.5
64
0.25
64
>32
0.25
>32
8
t011
mecA
>16
>4
4
≤0.25
0.5
32
0.5
>64
>32
0.25
>32
8
t011
mecA
>16
>4
2
≤0.25
1
32
0.5
16
>32
0.25
>32
8
t064
mecA
>16
-
>4
4
≤0.25
0.5
64
0.25
>64
>32
0.25
>32
8
t011
mecA
16
>16
>4
1
≤0.25
≤0.25
32
0.12
32
>32
0.25
>32
4
t011
mecA
2011 skin infection
>16
>16
>4
2
≤0.25
≤0.25
64
0.5
≤0.5
4
0.25
1
8
t011
mecA
2012 wound
>16
>16
>4
8
1
1
64
0.25
>64
>32
0.5
>32
8
t011
mecA
Horse
2012 wound
16
-
>4
1
≤0.25
0.5
32
0.25
32
>32
0.25
>32
4
t011
mecA
Horse
2013 abscess
>16
4
>4
>8
≤0.25
1
64
1
>64
>32
1
>32
16
t011
mecA
Horse
2014 wound
>16
>16
>4
4
≤0.25
1
64
0.25
64
>32
0.25
>32
8
t011
mecA
Horse
2014 post-op wound
>16
>16
>4
1
≤0.25
≤0.25
32
0.12
16
>32
0.25
>32
8
t011
mecA
Horse
2014 wound
>16
>16
>4
1
≤0.25
≤0.25
32
≤0.06
8
>32
0.25
>32
8
t011
mecA
Horse
2014 wound
>16
>16
>4
4
≤0.25
≤0.25
32
0.12
64
>32
0.25
>32
8
t011
mecA
Horse
2014 wound
>16
>16
>4
4
≤0.25
≤0.25
32
≤0.06
64
>32
0.25
>32
8
t011
mecA
Horse
2014 unknown
>16
>16
>4
2
≤0.25
≤0.25
32
0.12
32
>32
0.25
>32
8
t011
mecA
Horse
2014 post-op wound
>16
>16
>4
2
≤0.25
≤0.25
32
0.12
64
>32
0.12
>32
8
t011
mecA
Horse
2014 umbilical wound
>16
>16
>4
2
≤0.25
≤0.25
16
≤0.06
64
>32
0.25
>32
8
t011
mecA
Horse
2014 post-op wound
Pig
2010 snout
Cow
2010 milk screening
Cow
2010 milk screening
4
Cow
2010 milk screening
16
Cow
2011 milk screening
2
>16
Cow
2012 milk screening
>16
>16
Cow
2012 milk
>16
Cow
2013 milk screening
Cow
2014 milk screening
16
Fox
Pen
Cet
>16
-
>4
1
≤0.25
0.5
64
>16
>16
>4
1
≤0.25
0.5
32
>16
>16
>4
2
≤0.25
1
32
2008 post-op wound
16
>16
>4
2
≤0.25
1
2008 post-op wound
>16
>16
>4
2
≤0.25
0.5
Horse
2008 screening
>16
16
>4
2
≤0.25
Horse
2008 post-op wound
>16
8
>4
2
Horse
2008 post-op wound
2
>16
4
4
Horse
2009 wound
16
>16
>4
Horse
2009 post-op wound
16
>16
Horse
2010 post-op wound
>16
>16
Horse
2010 post-op wound
>16
>16
Horse
2010 post-op wound
>16
Horse
2010 wound
>16
Horse
2010 post-op wound
>16
Horse
2010 post-op wound
Horse
2011 post-op wound
Horse Horse
Hedgehog 2003 kidney Hedgehog 2011 skin infection
a
Antimicrobial a
Cli
Ery
Tet
Fus
16
>16
>4
4
≤0.25
≤0.25
32
≤0.06
64
>32
>4
>32
8
t011
mecA
>16
>16
>4
>8
0.5
1
64
0.5
>64
>32
0.25
>32
16
t011
mecA
4
16
2
1
≤0.25
≤0.25
≤0.5
0.25
≤0.5
2
0.5
2
8
t524
mecC
16
1
1
≤0.25
0.5
≤0.5
0.5
≤0.5
2
0.25
1
4
t524
mecC
>16
>4
4
≤0.25
0.5
≤0.5
0.25
≤0.5
2
0.5
2
8
t524
mecC
2
2
≤0.25
0.5
≤0.5
0.12
≤0.5
4
0.25
1
8 t9111
mecC
2
0.5
≤0.25
0.5
≤0.5
0.25
≤0.5
2
0.25
2
8
t002
mecA
16
>4
1
≤0.25
1
≤0.5
0.5
1
8
0.5
2
8
t002
mecA
1
8
0.5
0.5
≤0.25
1
≤0.5
0.5
≤0.5
4
0.5
2
8
t843
mecC
>16
>16
>4
2
≤0.25
>32
16
0.25
≤0.5
>32
0.25
2
8
t127
mecA
16
2
2
≤0.25
1
≤0.5
1
1
8
0.5
4
8 t5771
mecC
4
16
2
1
0.5
1
≤0.5
1
1
8
0.5
2
8
t843
mecC
Hedgehog 2014 lung
16
>16
2
1
≤0.25
≤0.25
≤0.5
≤0.06
≤0.5
2
0.25
1
8
t978
mecC
Hedgehog 2014 spleen
16
>16
2
2
≤0.25
≤0.25
≤0.5
≤0.06
≤0.5
2
0.25
0.5
8 t3391
mecC
Hedgehog 2014 skin infection
16
>16
2
2
≤0.25
≤0.25
≤0.5
0.5
≤0.5
4
0.5
1
16 t6300
mecC
Tested with 2% NaCl
SWEDRES | SVARM 2014
TABLE 2.8. Companion animals. Isolates of methicillin-resistant Staphylococcus aureus (MRSA) in Swedish dogs and cats up to and including 2014. All isolates were positive for the mecA or mecC and nuc genes by molecular methods. Shaded areas indicate MIC above EUCAST cut-off values. Animal species
Year
Clinical background/ Sampling site
Dog
2006
post-op wound
>16
>16
>4
8
≤0.25
0.5
≤0.5
Dog
2006
post-op wound
>16
>16
>4
8
≤0.25
0.5
≤0.5
Dog
2006
post-op wound
>16
8
>4 >8
≤0.25
0.5
≤0.5
Dog
2007
post-op wound
>16
>16
>4 >8
≤0.25
0.5
≤0.5
Dog
2007
abscess
>16
>16
>4 >8
≤0.25
0.5
≤0.5
Dog
2007
post-op wound
>16
>16
>4 >8
0.5
0.5
2
Dog
2007
post-op wound
>16
16
>4
8
≤0.25
0.5
≤0.5
Dog
2007
unknown
>16
16
>4 >8
≤0.25
0.5
≤0.5
Dog
2008
wound
>16
>16
>4 >8
≤0.25
1
Dog
2008
unknown
>16
>16
>4 >8
≤0.25
≤0.25
Dog
2008
unknown
>16
>16
>4 >8
≤0.25
Dog
2008
unknown
>16
>16
>4 >8
Dog
2009
post-op wound
8
>16
>4 >8
Dog
2009
wound
>16
>16
>4 >8
0.5
Dog
2010
wound
>16
>16
>4 >8
>32
Dog
2010
ear
8
-
>4 >8
≤0.25
Dog
2010
unknown
>16
16
>4
8
Dog
2010
skin
16
16
>4
1
Dog
2013
wound
4
>16
>4
Dog
2013
wound
16
>16
Dog
2013
wound
>16
>16
Dog
2013
unknown
>16
Dog
2013
wound
Dog
2014
wound
Dog
2014
Dog Cat
Antimicrobial Oxa
Fox
Pen Cet
Cli
Ery
Tet
Fus
Chl
spatype
mecgene
Gen
Kan
Cip
Tmp
0.5
≤0.5
2
>4
1
8 t032
mecA
0.5
≤0.5
2
>4
1
8 t032
mecA
0.25
1
4
>4
2
8 t032
mecA
0.5
≤0.5
4
>4
2
8 t032
mecA
0.5
≤0.5
2
>4
1
8 t032
mecA
-
1
2
>4
2
4 t032
mecA
0.25
≤0.5
2
>4
1
8 t032
mecA
0.25
≤0.5
4
>4
2
8 t032
mecA
≤0.5
0.25
1
2
>4
2
8 t032
mecA
≤0.5
0.5
1
2
>4
1
8 t032
mecA
1
≤0.5
0.25
1
2
>4
2
8 t032
mecA
0.5
>32
≤0.5
0.5
32
>32
>4
>32
16 t127
mecA
≤0.25
0.5
≤0.5
0.25
≤0.5
2
>4
2
8 t032
mecA
1
1
0.5
1
4
>4
4
16 t032
mecA
>32
≤0.5
0.5
1
>32
>4
2
16 t002
mecA
0.5
≤0.5
0.5
≤0.5
2
>4
1
8 t032
mecA
≤0.25
>32
≤0.5
0.5
≤0.5
2
>4
8
4 t020
mecA
≤0.25
≤0.25
≤0.5
8
1
2
0.5
2
8 t002
mecA
1
≤0.25
>32
16
0.25
2
>32
0.25
2
8 t127
mecA
>4
2
≤0.25
1
≤0.5
0.5
≤0.5
2
0.5
4
8 t304
mecA
>4
2
≤0.25
1
≤0.5
0.25
≤0.5
4
0.5
2
8 t127
mecA
>16
>4 >8
0.5
1
1
1
1
4
>4
4
8 t032
mecA
16
>16
>4
2
≤0.25
0.5
≤0.5
0.5
≤0.5
2
0.5
>32
8 t223
mecA
16
>16
>4
2
≤0.25
1
16
0.5
1
8
0.5
4
8 t325
mecA
unknown
>16
>16
>4
8
≤0.25
≤0.25
≤0.5
≤0.06
≤0.5
2
>4
1
8 t032
mecA
2014
unknown
>16
>16
>4
1
≤0.25
>32
≤0.5
≤0.06
≤0.5
2
0.25
1
8 t002
mecA
2009
urine
>16
>16
>4 >8
≤0.25
0.5
≤0.5
0.25
≤0.5
0.5
>4
4
4 t032
mecA
Cat
2009
unknown
>16
>16
>4 >8
≤0.25
0.5
≤0.5
0.5
1
1
>4
2
8 t032
mecA
Cat
2010
ear
>16
-
>4 >8
≤0.25
0.5
≤0.5
1
≤0.5
2
>4
1
8 t032
mecA
Cat
2010
nose
>16
16
>4 >8
≤0.25
≤0.25
≤0.5
0.25
≤0.5
1
>4
1
8 t032
mecA
Cat
2011
skin infection
>16
>16
>4 >8
≤0.25
≤0.25
≤0.5
0.25
≤0.5
2
>4
1
8 t022
mecA
Cat
2012
wound
>16
>16
>4 >8
≤0.25
≤0.25
≤0.5
0.25
≤0.5
4
>4
2
8 t032
mecA
Cat
2012
wound
>16
>16
>4 >8
0.5
1
1
1
1
4
>4
2
16 t032
mecA
wound
a
Cat
2013
Cat
2014
wound
8
>16
1
2
≤0.25
≤0.25
≤0.5
0.25
≤0.5
2
0.25
0.5
8
t978
mecC
Cat
2014
unknown
8
>16
2
1
≤0.25
≤0.25
≤0.5
≤0.06
≤0.5
1
0.25
0.5
8
t978
mecC
b
a
Tested with 2% NaCl; b The isolate was not available for further laboratory analyses.
57
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MRSA in pigs in Sweden
In focus
MRSA in pigs MRSA of clonal complex 398 (CC 398) is widespread in pigs in many countries and pigs are mostly carriers without clinical symtoms. The bacteria are spread by direct or indirect contact and therefore trade of live pigs is an obvious risk factor for occurrence of MRSA in pig herds (Crombé et al., 2013). Use of antibiotics and large herd size are also associated with a higher risk of MRSA (Crombé et al., 2014). Hitherto few efforts have been made to mitigate or control MRSA in pigs. An exception is Norway where MRSA is controlled by depopulation of positive farms and cleaning and desinfection of premeses before restocking. (http://www.mattilsynet.no). In Sweden, the aim is so far to counteract introduction and spread of MRSA in pig herds. To this end pig farmers and their employees have been informed on MRSA CC398 and adviced on biosecurity measures to mitigate its introduction to pig herds. Also, breeding pigs traded from other countries are quarantained and tested for MRSA before introduced to herds in Sweden. Similarly, semen traded from other countries is tested for MRSA.
Screening studies in Swedish pigs Five screening studies have been performed in different categories of pigs in Sweden: • 100 herds producing pigs for slaughter were sampled in 2006-2007. • 208 production herds and breeding herds were sampled in an EU baseline study in 2008. • Pigs from 191 herds were sampled at slaughter in 2010. • All 53 nucleus and multiplying herds were sampled in 2011. • All 39 nucleus and multiplying herds were sampled in 2014. Of all samples taken, MRSA was only found in one pooled sample from five pigs from one herd at slaughter in 2010. Since the sampling was performed blindly, the herd was not known and no measures were taken. Nucleus and multiplying herds are selling live animals to several other herds further down in the pig production pyramid. Since trade of live animals is an important risk factor for transmission of MRSA, these types of herds are of key importance for controlling spread of MRSA in pigs. All Swedish nucleus and multiplying herds pre-
sent were subjected to sampling, 53 herds in 2011 and 39 herds in 2014. Weaned pigs in the age 5-12 weeks were sampled, 6 pigs per box, 15 boxes per herd. Sampling was done by scrubbing the skin behind one ear with a sterile compress. The same compress was used to all 6 pigs in the same box, constituting a pooled sample. In general, samples were analysed in accordance with the method in the EU basline study, in a two step selective enrichment, followed by plating on selective media and blood agar plates. MRSA was not found in any sample. Hence, there are reasons to believe that the MRSA situation in the Swedish pig population still is favourable. The low number of notified human cases of MRSA CC398 (21 cases in 2014) supports this opinion. However, continuous monitoring in pigs is of importance as the situation can change rapidly.
Consequences of MRSA in pigs The problem with MRSA CC398 in pigs is not primarily infections in pigs, but instead that the pig population may constitute a reservoir with risk of spread to humans. People in direct or indirect contact with live pigs carrying MRSA CC398 are at risk to become carriers of such bacteria. In regions where MRSA is prevalent among pigs, pig farmers and their employees, veterinarians, animal transporters and slaughter house workers may therefore be considered a risk group for MRSA carriage. This applies also to household members of these professional categories. Carriage of MRSA CC398 in humans implies a risk for infections that are difficult to treat, but may also cause anxiety and stigmatisation. Moreover, colonized and infected people in contact with health care may generate increased societal costs if precautionary measures to prevent further spread are taken.
Societal benefits from preventing MRSA in pigs In a scenario were MRSA has been introduced, spread and established in the Swedish pig population, it is likely that people with professional contact with live pigs would be classified by the health care as a risk group for MRSA carriage. This would imply societal costs in the health care. A study was performed in order to estimate these costs, and also to estimate the costs for preventing introduction of MRSA to Swedish pigs through import of breeding pigs (Höjgård et al., 2015).
SWEDRES | SVARM 2014
The future When first detected in 2004, MRSA CC398 was already widely spread among pigs in several countries. However, there are indications that the situation in the Swedish pig population still is favourable, as stated above, and efforts to mitigate spread among pis in Sweden may therfore be relevant and warranted. Hence, from a public health perspective there would be good reasons to prevent spread of MRSA to pigs in Sweden.
In focus
The risk group was estimated to about 6 000 persons. The extra costs these persons would generate in contact with primary care and in-patient care due to MRSA sampling, precautionary measures, contact tracing and treatment were calculated. These costs would be the potential societal benefits from preventing introduction of MRSA to pigs. Likewise, the costs for preventing introduction through sampling of imported breeding animals and destruction of positive animals were calculated. The societal benefits were estimated to between € 871 000 and € 1 233 000 and the costs to € 211 000, giving a net societal benefit of between € 660 000 and € 1 022 000 annualy. As there were several factors that were not known, the calculations were partly built on assumptions, but the results indicate that under Swedish conditions the societal benefits exceed the costs for preventing introduction of MRSA CC398 through import of pigs.
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Zoonotic aspects on MRSP
Methicillin-resistant Staphylococcus pseudintermedius (MRSP) MRSP in animals Methicillin-resistant Staphylococcus pseudintermedius (MRSP) was first isolated in Sweden from a healthy dog in 2006. Therafter a large increase in the numbers of notified MRSP cases was observed and the highest number was observed in 2009 with 130 cases (Figure 2.13). However, since 2010 the number of cases has dropped successively with only 33 cases notified in 2013, but in 2014 the reported cases increased to 39. In 2014 the isolates were from 36 dogs, 2 cats and 1 horse. In 2014, 34 of the 39 notified MRSP isolates were available at SVA for further epidemiological typing and antimicrobial susceptibility testing. The origins of isolates were unknown in 8 of the cases, 11 were from wounds, 7 from skin including ears. The remaining isolates were from, ungual crest (n=2), urine (n=2), eye (n=1), milk sample (n=1), tonsil (n=1) and lung (n=1). Based on spa-typing 47% of the isolates were shown to belong to the European clone ST71-J-t02-II-III, described by Perreten et al. (2010), belonging to spa type t02. Of the remaining isolates 35% was nontypeable and three isolates belonged to t05, two to t10 and one to a new spa-type. All nontypeable isolates were subjected to MLST, two isolates were shown to be ST71, four belonged to ST258, one to ST45, one to ST298 and four belonged to new MLSTs. The ST258 is of specific interest because it has been described as an emerging clone in Denmark and Norway (Osland et al., 2012; Damborg et al., 2013). After MRSP was first detected in Sweden the occurrence was dominated by the European clone ST71-J-t02-II-III, but during the last couple of years the occurrence of this clone has decreased and the diversity of MRSP has increased. All isolates were defined as multi-resistant, but 91% were susceptible to fusidic acid, 32% to gentamicin and 100% to tetracycline and nitrofurantoin. The isolates belonging to the ST71-J-t02-II-III clone were all susceptible to fusidic acid, with the exception of one isolate, one of the ST71 nontypeable by spa-typing. FIGURE 2.13. Blue line represents the number of cases with methicillinresistant Staphylococcus pseudintermedius (MRSP) in Sweden notified to the Swedish Board of Agriculture 2008-2014. In 2006-2007 the numbers represent the isolates that were sent to SVA and confirmed as mecA-positive. Red squares represent the percent of isolates likely belonging to the European clone ST71-J-t02-II-III, complete data only available for 2008-2009 and 2013-2014. 140
100
120
80
100 60
80 60
40
40 20
20 0
0 2006 2007 2008 2009 2010 2011 2012 2013 2014
Percent likely ST71
Number of cases of MRSP
60
Staphylococcus pseudintermedius is not considered to be a zoonotic pathogen, but there are several reports of MRSP infections in humans with a varying degree of severity. Furthmore, in a recent study it was shown that out of 101 isolates defined as S. aureus from infected dog bites by clinical microbiology laboratories, 13% were actually S. pseudintermedius (Börjesson et al., 2015). One of the isolates was multi-resistant belonging to ST118. In 2011 there were four cases of MRSP infections in hospitalised patients at Uppsala University hospital without any established animal-human contact (Starlander et al., 2014).
Vancomycin resistant Enterococcus faecalis and Enterococcus faecium (VRE) VRE in humans Background
Vancomycin resistant enterococci (VRE) are important causes of nosocomial infections in many parts of the world, usually involving high-risk populations such as immunocompromised and intensive care patients. Like MRSA, VRE were made notifiable according to the Swedish Communicable Disease Act in the year 2000 and since 2004 contact tracing is mandatory. The following presentation is based on data collected in the national web-based notification system SmiNet. During the last seven years an active effort has been made to improve the quality of data and to collect missing data. The notifications have been reviewed and complemented relevant epidemiologic information from investigations around each case in collaboration with the CMOs. From 2000 to 2006 only low numbers (18-35 per year) of VRE-cases were reported in Sweden. In 2007, reports came from Stockholm County about an increase in the number of VRE-cases, and the total yearly count was 53 cases (Table 2.9, Figure 2.11). This was the beginning of an outbreak that would last until 2011, when it was finally declared to have come to an end in the affected counties. The outbreak has been described in SWEDRES 2011 and elsewhere (Söderblom et al., 2010). The total number of cases with a strain of Enterococcus faecium with vanB belonging to this outbreak was 872. The next large outbreak occurred in Västernorrland County and lasted 2010-2011 with an estimated number of 100 cases. It was caused by another strain of E. faecium still with a vanB gene. In 2012 at least two outbreaks caused by two different strains of E. faecium with vanA genes contributed to the increase in this type of VRE. These outbreaks occurred in Jönköping and Halland counties, respectively, and led to extensive infection control measures to limit and eradicate the outbreak strains (SMI Newsletter 2013).
SWEDRES | SVARM 2014
Notifications of VRE according to the Communicable Disease Act
During 2014 a total of 402 cases were reported, an increase by 77% compared to 2013 (Table 2.9). Although VRE cases were reported from 19 of the 21 Swedish counties the increase was largely due to one major hospital outbreak in Gävleborg that started in 2013 and continued during 2014. The average national incidence of VRE was 4.1 with higher than average incidence figures in Gävleborg (76.4), Uppsala (10.9) and Kronoberg (7.4) counties. Of all cases, 330 (82%) were reported as domestic (Figure 2.14), and of those 311 were healthcare related. In 69 cases (17%) VRE had been acquired abroad. The most common countries for imported VRE infection were Serbia (11 cases), Turkey (9), Greece (8) and Germany (4). Sixty-three (91%) of the imported cases were healthcare related. The domestic VRE cases were detected through contact tracing (71%), screening (18%) or clinical symptoms (4%). For six percent of the domestic cases, indication for sampling was not stated. The majority of the imported cases (90%) were detected through screening, four percent due to clinical symptoms and none due to contact tracing. Accordingly a majority of the isolates (92%) in the first laboratory notifications were from feces and rectum, and only four percent from urine, wound or other clinical samples. More cases were notified from men (55%) than from women (45%), with the median age for women 76 years and for men 75 years.
FIGURE 2.14. Number of human cases of VRE annually notified in Sweden 2006-2014 by country of infection. Numbers of reported cases are shown in brackets. 700
Number of cases
600 500 400 300 200 100 0
2006 (24)
2007 (53)
2008 (617)
2009 (402)
Domestic
2010 (214)
2011 (122)
Imported
2012 (152)
2013 (227)
2014 (402)
No data
The median age was lower for imported (66 years) than for domestic cases. In 2014, isolates from 394 cases carried E. faecium and isolates from 9 cases E. faecalis. In a sample from one case both E. faecium and E. faecalis could be isolated. As in 2013, the dominating resistance gene 2014 was vanB (Table 2.9). Invasive VRE infection was reported in seven cases in 2014. All were in newly notified persons. Epidemiological typing of VRE in outbreaks
For enterococci PFGE is still used as the standard typing method. Isolates from notified cases in all counties from 2007 and onwards have been analysed, and comparisons with isolates from previous years have also been performed. From this national strain collection and PFGE database it has been shown that the E. faecium with vanB gene causing the outbreak situation 2007-2010 had not been detected before 2007. This strain was named SE-EfmB-0701 to indicate species (Efm), resistance gene (B), year of detection (07) and a serial number (01). Several smaller outbreaks in Sweden during 2000 – 2006 had been caused by strains of different PFGE-types, and they were given names retrospectively. The extensive outbreak 2010-2011 in Västernorrland County was caused by a strain with the PFGE-type SE-EfmB-1001. In 2012 the first extensive outbreaks caused by vanA-producing E. faecium occurred in Jönköping (SE-EfmA-1203), Halland (SE-EfmA-1204) and Stockholm counties (several types) with a total of around 50 cases. (SMI Nyhetsbrev 2012). In 2014, thirteen healthcare related outbreaks of E. faecium were reported from six counties; seven outbreaks with vanA gene and six with vanB gene. The seven vanA outbreaks affected 2-19 patients each, and six vanB outbreaks affected 2-225 patients. The largest outbreak started in Gävleborg county in september 2013, and lasted to the end of 2014. A total of 314 cases have been reported from this outbreak caused by a strain typed as SE-EfmB-1308. http:// www.folkhalsomyndigheten.se/amnesomraden/beredskap/ utbrott/utbrottsarkiv/vankomycinresistenta-enterokockergavleborg-2013-2014/ The regular typing of VRE from all new cases makes the national PFGE database useful in identifying outbreak strains among the relatively large number of isolates with so called “unique” PFGE patterns.
TABLE 2.9. VRE-notifications according to the Communicable Disease Act 2007-2014 by species and van-gene. Species and R-gene
2007
2008
2009
2010
2011
2012
2013
2014
E. faecium vanA
12
96
61
63
39
97
93
110**
E. faecium vanB
38
505
326
135
70
26
126
E. faecalis vanA
2
4
6
3
8
5
1
1
2
E. faecalis vanB Not specified Total
1 53
3 5***
12
9
12
3
24
617
402
214
122
152
In one case in 2013 a strain of E. faecium with both vanA and vanB gene was detected. ** In two cases in 2014 a strain of E. faecium with both vanA and vanB gene was detected. *** In one case in 2014 both E. faecium vanB and E. faecalis vanB could be isolated. *
,
281** ***
7 227
*
6 402
61
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SWEDRES | SVARM 2014
VRE in animals
Notifications according to the Communicable Disease Act
No specific screening for vancomycin resistant enterococci (VRE) was performed in 2014. However, in the monitoring of indicator bacteria from healthy animals all isolates of Enterococcus faecalis and Enterococcus faecium are tested for susceptibility to vancomycin. In 2014, samples from broilers were investigated and one isolate of E. faecium had MIC above ECOFF (8 mg/L). The isolate was further investigated by PCR but vanA or vanB genes were not detected (see Resistance in indicator bacteria from animals for details). Historically, vancomycin resistant E. faecium with the vanA gene has been isolated from intestinal content of healthy broilers but not from other farm animals studied in Svarm. For further information regarding VRE in broilers see Svarm 2011; Vancomycin resistant enterococci (VRE) in Swedish broiler production – a summary.
In 2014 a total of 70 PNSP cases were reported in Sweden. Forty-six percent of the cases had been infected domestically and 31% of the cases in a foreign country. For the remaining 16 cases (23%) no country of acquisition was given. The incidence of PNSP in Sweden 2014 was 0.7 cases per 100 000 inhabitants. The majority of PNSP cases (34% in 2014), independent of year observed, are found in the age group 0-4 years. Of the reported cases in 2014, 60% have been male, 40 % female. PNSP were reported from 16 of 21 Swedish counties, with Stockholm (17 cases), Kalmar (8 cases) and Skåne (6 cases) accounting for 44% of all notifications. The remaining 13 counties reported 1-5 cases each. PNSP, were most often found in cultures from the nasopharynx. In 33 cases (47%) the detection of PNSP was due to clinical infection. Seven cases were detected through contact tracing and 6 cases through targeted screening. In the remaining cases another reason for sampling was stated (7 cases) or the information was missing (17 cases).
Zoonotic aspects on VRE Previous data from Svarm have shown that E. faecium with the vanA gene are present among Swedish broilers. There is a potential risk for transfer of these VRE to humans. However, in studies comparing PFGE-patterns from human and broiler isolates no common type has been found. Accordingly, there are no indications that the presence of VRE in broilers in Sweden has affected the situation in Swedish healthcare.
Streptococcus pneumoniae with reduced susceptibility to penicillin (PNSP) PNSP in humans Background
Streptococcus pneumoniae with reduced susceptibility to penicillin (PNSP, defined as MIC ≥ 0.5 mg/L) became notifiable according to the Communicable Disease Act in 1996. In May 2012, a revised case definition was introduced, stating that only PNSP with MIC of penicillin > 1 mg/L were now notifiable and the identified cases subjected to contact tracing. However, all pneumococcal isolates with MIC ≥ 0.5 mg/L are still collected by the Public Health Agency of Sweden for serotyping.
Serotype distribution
In 2014, three cases of invasive PNSP infection, with bacteria isolated from blood were reported (MIC > 1 mg/L). These were of serotypes 6B, 9N and 11A. For all cases of PNSP with MIC ≥ 0.5 mg/L (227 isolates serotyped so far) the most common serotypes were in descending order: 19F (24%), non-typable (NT) (17%), 35B (12%), 19A (9%), 23F (6%), 14 (5%), 11A(4%), 6B(4%) and 9V(4%).
SWEDRES | SVARM 2014
Zoonotic pathogens Zoonoses are diseases and infections that can be naturally transmitted between animals and humans. Antibiotic resistance in zoonotic bacteria such as Salmonella and Campylobacter from animals is therefore of direct public health concern.
Salmonella Salmonella from human clinical specimens Infection with Salmonella in humans is a notifiable disease in Sweden, and the focus has been on epidemiological typing in order to facilitate contact tracing. Antibiotic susceptibility testing on isolates derived from fecal cultures has only been monitored locally by a few laboratories. Since a majority of the Salmonella strains isolated in Sweden originate from persons who were infected when travelling abroad, it has been anticipated that their resistance patterns most probably reflect the situation at their geographical origin. Blood culture isolates of Salmonella are always tested, and in 2014 we used the complete data sets of positive blood cultures from seven laboratories (see background information) as one source of information on antibiotic susceptibility in Salmonella. In 2014, 61 isolates of Salmonella were found among a total of 12609 blood cultures. The most common serovars were S. Typhi (14), S. Enteritidis (8), S. Panama (3), and S. serogroup C and D, S. Typhimurium (3) with 3 isolates from each (Table 3.1). Nineteen of the cases were reported as travel associated, with Thailand, India, Africa (north or central regions), Turkey, Bali and Nepal being the countries/regions mentioned.
Table 3.1. Salmonella from blood cultures in Sweden 2014. Data collected from reporting laboratories covering apporximately 48 % of the Swedish population. Salmonella serovar
S. Typhi
S. Enteritidis
No of isolates
No of No of isolates Cip-R tested for Cip
No of No of Countries isolates Tsu-R reported tested (no) for Tsu
14
13
9
14
8
8
3
8
2
India (3), Nepal (1), Thailand (1), Zambia (1)
3
Thailand
S. Panama
3
3
3
S. Serogroup C
3
2
3
S. Serogroup D
3
2
S. Typhimurium
3
2
S. Heidelberg
2
2
S. Stanley
2
2
2
2
S. other serovars
23
20
5
22
6
Total
61
54
20
60
12
1
3
Ghana 1
Unspecified travel
3 2
Africa (1), Bali (1), India (1), Kenya (1), Marocko (1), Sri Lanka a Cip-R = ciprofloxacin resistant; Tsu-R = trimethoprim-sulfa resistant (1), Thailand (3), Turkey (1)
Susceptibility testing by disk diffusion and application of NordicAST breakpoints was performed by local clinical laboratories. No isolate was resistant to cefotaxime. Resistance to trimethoprim-sulphametoxazole was found in 12 isolates (20%) and resistance to ciprofloxacin in as many as 19 (37%). Nine of 13 S. Typhi isolates tested for ciprofloxacin susceptibility were resistant to ciprofloxacin (MICs 0.25-32 mg/L) but resistance was also found among isolates of other serovars (Table 3.1).
Salmonella in animals Findings of Salmonella in animals are notifiable in Sweden. In Svarm, antibiotic susceptibility is determined in one isolate from each warm-blooded animal species (wild and domesticated) involved in incidents notified 2014. Isolates from incidents previously notified but still under restrictions in 2014 are also included. In incidents involving more than one serovar, one isolate of each serovar is tested. As from 2014 phage typing is not performed on isolates of Salmonella from animals. For details on methodology see Materials and methods, resistance in bacteria from animals. All animals 2014
Altogether, 77 isolates were tested of which 21 were S. Typhi murium (Table 3.2). Distributions of MICs and resistance in all isolates are presented in Table 3.3 and for the subset S. Typhimurium in Table 3.4. The majority of isolates (75%) were susceptible to all antimicrobials tested, but 19 isolates were resistant to at least one substance and five isolates (6%) were multiresistant. Two isolates of S. Typhimurium from wild birds were phenotypically resistant to ESC. In both isolates the MIC of ceftazidime was 2 mg/L and in one of the isolates the MIC of cefotaxime was 1 mg/L. Ampicillin MIC was 32 mg/L in both isolates. However, on testing with PCR no genes coding for transferable ESC resistance were detected. The five multiresistant isolates were S. Typhimurium from cattle (Table 3.5). One of the isolates was resistant to ampicillin, ciprofloxacin, chloramphenicol, florfenicol, gentamicin, streptomycin, sulphonamide and tetracycline. Salmonella with this phenotype has previously not been isolated from animals in Sweden (Table 3.6) and it is an uncommon phenotype also in other countries in EU (EFSA & ECDC, 2015). Three isolates were resistant to ampicillin, streptomycin, sulphonamide, tetracycline and in addition to quinolones (ciprofloxacin and nalidixic acid). One of the isolates from 2014 was from an incident notified in already in 2013 and still under restrictions. Hence, Salmonella with this phenotype has been isolated only from three incidents in animals in Sweden (Table 3.6). This resistance phenotype is uncommon also in other countries in EU (EFSA & ECDC, 2015). One isolate was resistant to ampicillin, chloramphenicol, florfenicol, streptomycin, sulphonamide and tetracycline. This is one of the most common MDR-phenotypes of S. Typhimurium in EU and is often associated with S. Typhimurium of phage type DT 104 (EFSA & ECDC, 2015). Such strains have on several occasions been isolated from cattle, pigs and sheep in Sweden (Table 3.6).
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SWEDRES | SVARM 2014
Table 3.2. Number of Salmonella enterica isolates tested for antibiotic susceptibility, 2014. Serovar
Cattle
Poultry
Horses
Dogs
S. Derby
Cats
Wild birds
Wild mammals
Total 1
1
S. Dublin
13
13
S. Duesseldorf
2
2
S. enterica subsp. diarizonae (IIIb)
4
4
S. Enteritidis
7
7
S. Infantis
1
S. Mbandaka
1
1 2
1
S. Newport
1
1
S. Poona
1
1
S. Typhimurium
6
5
21
7
1
27%
9%
1%
S. enterica subsp. enterica (I)
Percent of total
43
12
19
77
16%
25%
100%
11
2
15
3%
19%
1
Total
6
15
2
1
Farm animals 2000-2014
The majority (73%) of S. Typhimurium isolates from the incidents in farm animals has been susceptible to all antibiotics tested but 34 (11%) were multiresistant (Table 3.6). The most common resistance traits were ampicillin, streptomycin, tetracycline, sulphonamide, chloramphenicol and florfenicol. Resistance to third generation cephalosporins has not been found and resistance to ciprofloxacin has been confirmed in isolates from only five incidents. Six isolates (2%) of other serovars than Typhimurium have been multiresistant. The 34 multiresistant isolates of S. Typhimurium in the period 2000-14 were from 32 separate incidents of which 21 involved cattle, 6 pigs, 2 poultry and 1 incident involved both
From a public health perspective, resistance in Salmonella from farm animals is of greater concern than resistance in isolates from wild animals or pets. This is because bacteria from animals raised for food production can contaminate carcasses at slaughter and thereby be transmitted to humans through the food chain. In the period 2000-2014, isolates from the vast majority of notified incidents in farm animals were tested in Svarm, in total 622 isolates. About half of the isolates, 306 (49%), were S. Typhimurium and of these 38% were from pigs, 33% from cattle, 27% from poultry and 2% from sheep.
Table 3.3. Distribution of MICs and resistance (%) in Salmonella enterica (n=77) from all animals, 2014. Antimicrobial
Resistance %
Ampicillin
9
Cefotaxime
1
Ceftazidime
3
Chloramphenicol
3
Ciprofloxacin
5
Colistin
5
Florfenicol
3
Gentamicin
1
Kanamycin
0
Distribution (%) of MICs (mg/L) ≤0.008 0.016 0.03 0.06 0.12 0.25 0.5
1.3
7.8 36.4 45.5 6.5
1.3
51.9 33.8
1
2
89.6
1.3
4
40.3
13.0 40.3
1.3
16
32
64
128 256 512
2.6
1024
>1024
6.5
1.3 9.1
2.6
2.6
26.0 68.8 1.3
8
2.6
2.6
3.9 35.1 44.2 15.6
3.9
1.3
72.7 24.7
2.6
1.3 76.6 18.2 2.6
1.3 100
Nalidixic acid
4
7.8
83.1
5.2
Streptomycin
18
1.3
1.3
1.3 77.9 11.7
3.9
Sulphamethoxazole
8
Tetracycline
6
Trimethoprim
0
1.3
1.3 61.0 33.8
90.9
2.6
2.6
1.3
2.6
3.9
16.9 48.1 24.7 1.3 1.3
5.2
1.3
6.5
SWEDRES | SVARM 2014
Table 3.4. Distribution of MICs and resistance (%) in Salmonella Typhimurium (n=43) from all animals, 2014. Antimicrobial
Resistance %
Ampicillin
16
Cefotaxime
2
Ceftazidime
5
Chloramphenicol
5
Ciprofloxacin
9
Colistin
0
Florfenicol
5
Gentamicin
2
Kanamycin
0
Nalidixic acid
7
Streptomycin
14
Sulphamethoxazole
12
Tetracycline
12
Trimethoprim
0
Distribution (%) of MICs (mg/L) ≤0.008 0.016 0.03 0.06 0.12 0.25 0.5
1
2
4
8
16
83.7 44.2 46.5 4.7
2.3
32
64
4.7
2.3
>1024
11.6
4.7
25.6 69.8 16.3 32.6
1024
2.3
41.9 39.5 11.6 2.3
41.9
128 256 512
4.7
7.0 37.2 53.5 9.3 83.7 11.6
4.7
79.1 18.6
2.3 100 2.3
88.4
2.3
7.0 86.0
88.4
2.3
4.7
7.0
9.3
46.5 30.2 2.3
2.3
9.3
11.6
60.5 39.5
Table 3.5. MICs (mg/L) in Salmonella enterica resistant to three or more antibiotics, 2014. Shaded fields indicate resistance. Source Serovar
Amp
Ctx
Caz
Cip
Nal
Chl
Flo
Col
Gen
Kan
Cattle
S. Typhimurium
>128
0.25
1
0.12
8
>64
>32
1
>16
≤8
Cattle
S. Typhimurium
>128
0.12
0.5
0.06
4
>64
>32
2
1
≤8
128 >1024
32
0.5
Cattle
S. Typhimurium
>128
0.06
1
0.5
32
4
8
1
1
≤8
>256 >1024
>128
0.25
Cattle
S. Typhimurium
>128
0.06
0.5
0.5
32
4
8
≤0.5
0.5
≤8
>256 >1024
>128
0.25
Cattle
S. Typhimurium
>128
0.12
0.5
0.5
32
4
8
1
1
<8
>256 >1024
>128
0.25
pigs and cattle. Of the two remaining incidents, one was in sheep and one in ducks in a hobby flock. Three incidents in 2004 involved cattle and were epidemiologically linked through trade of calves. An epidemiological link was also suspected between four incidents 2007-2008 involving cattle, pigs and sheep. There are no known links between the other incidents. Figure 3.1. Resistance (%) in Salmonella Typhimurium from all animals, 2000-2014. The number of isolates each year varies (n=31-85). 45% 40% 35%
25% 20% 15% 10% 5%
Streptomycin Sulfametoxazole
2014
2013
2012
2011
2009
Ampicillin Chloramphenicol
2010
2007
2008
2006
2005
2003
2004
2001
2002
0% 2000
Sul
Tet
Tmp
128 >1024
>128
0.5
In 2014 monophasic S. Typhimurium I (O 4,5,12:i- /O 4,5:i:/ O 4:i:-) was not isolated. However, nine incidents of monophasic S. Typhimurium have been confirmed in farm animals since this variant was first found in Swedish animals in 2006 (Table 3.6). Three incidents involved cattle, three incidents pigs, one incident ducks, and one incident involved both cattle and poultry. In five incidents isolates have had the resistance phenotype ampicillin, streptomycin, sulphonamide and tetracycline (Table 3.6). Monophasic S. Typhimurium has also been isolated from three dogs and a wild bird. Epidemiological links have been confirmed between some of the incidents of monophasic Salmonella.
Zoonotic aspects
30% Resistance
Str
Tetracycline
Occurrence of Salmonella among farm animals, as well as among other animals, is low in Sweden and few incidents involve multiresistant strains. Notably, transferable ESC resistance has never been found. Resistance to fluoroquinolones is rare but it is worrying that in the last two years three incindents in cattle involved multiresistant S. Typimurimum with a resistance phenotype that includes fluoroquinolones. The overall situation is however still favorable. This is largely due to the effective strategies in the Swedish salmonella control programme initiated in the 1950-ies.
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SWEDRES | SVARM 2014
Table 3.6. Resistance phenotypes of Salmonella Typhimurium (n=305) from incidents in farm animals, 2000-2014. All isolates were tested for susceptibility to ampicillin, florfenicol, gentamicin, chloramphenicol, ciprofloxacin, nalidixic acid, streptomycin, sulphamethoxazole, tetracycline, trimethoprim and to ceftiofur or cefotaxime.
AmpStrSul
Cattle
StrSulTet
Cattle
AmpSul
Cattle
AmpSul
Pigs
StrGen
Cattle
StrGen
Pigs
StrGen
Poultry
StrSul
Pigs
StrSul
Poultry
SulTm
Cattle
Amp
Poultry
Gen
Poultry
Nal
Pigs
Str
Cattle
Str
Pigs
Str
Poultry
Tet
Pigs
Susceptible
Cattle
4
Susceptible
Pigs
1
Susceptible
Poultry
1
Susceptible
Sheep
1
Sum
1
1
1
1
1
3
10
1
5 1 1 3
3 1
2
1 1
2
5
1
1
2
3
1
2 1
1 2
2
1
1 1
1
1
1
1
1 1
2
1 2
2
2
1
1 1
1
4
3
1
1
2
1
1
4 4
2
1
1
8
2
17 5
3
1
1
7
1 1
1
1
2
1
1
6
2
33
5
1
5
1
4
2 2
2
2
Sum
Poultry
Monophasic
Pigs
AmpStrSulTet
Not typed
AmpStrSulTet
NT
Cattle
NST (U277)
AmpStrSulTet
NST
1
Cattle
195
Cattle
AmpStrSulTetCipNal
193
AmpStrSulTetChl
146
1
126
Sheep
125
AmpStrSulTetChlFlo
120
4
99
6
Pigs
41
Cattle
AmpStrSulTetChlFlo
40
AmpStrSulTetChlFlo
39
Cattle
12
AmpStrSulTetCipChl FloGen
10
Pigs
9
Source
AmpStrSulTetCip NalChlFlo
7
Phenotype
110b
104
15a
Phagetype
1
66
3
1
1
44
Compiled data on occurrence and susceptibility of Salmonella from humans in Sweden is largely lacking. It is therefore not possible to comprehensively relate the situation in Swedish animals to the situation in humans. However, of the most common serovars from human invasive infections in 2014 (Table 3.1) S. Typhi is a serovar that is not associated with animals. Also, other serovars from human invasive infections e.g. S. Enteritidis, are most rare in animals in Sweden.
19
1
2
5
1
8 1
1
22
1
1
1
2
20
1
1
2
1
1
1
1
10
1
17
1
2
14
87
1
42
1
4
9
40
2 101
3
11
1
63
26
3
4
48
9 305
Moreover, over one third of the human isolates from the reporting laboratories in 2014 were resistant to ciprofloxacin. This high rate is in contrast to the rare findings of ciprofloxacin resistance in Salmonella from animals in Sweden. Taken together, this strongly suggests that Salmonella causing human invasive infections rarely originate from Swedish animals.
SWEDRES | SVARM 2014
Campylobacter
Of the 102 isolates tested, 92 were susceptible to all six antibiotics. Resistance to fluoroquinolones only (ciprofloxacin and nalidixic acid) was the most common phenotype (Table 3.7). Four isolates were resistant to nalidixic acid but not to ciprofloxacin, however the MIC of ciprofloxacin was slightly elevated for these isolates (0.5 mg/L). This has been described previously and in one study the majority of the isolates with the same phenotype had an Thr-86 →Ala mutation in gyrA instead of the more common Thr-86 → Ile mutation (Griggs et al., 2005). In comparison to previous years quinolone resistance increased notably in 2010 and 2012 but has declined 2014 (Figure 3.2). The reasons for this are not known but selection through use of antibiotics is unlikely as a single explanation since fluoroquinolones are seldom used in broiler production in Sweden. Further monitoring to follow up the finding is needed as well as further studies to elucidate the epidemiology of fluoroquinolone resistant C. jejuni.
Campylobacter in humans Data on antibiotic resistance in Campylobacter from humans is largely lacking. During 2014 29 cases of Campylobacter were reported from five laboratories delivering data from blood cultures. Resistance to erythromycin was found in one case and resistance to ciprofloxacin in four cases. None of the isolates tested were resistant to both of these antibiotics.
Campylobacter in animals The isolates of Campylobacter jejuni tested are from caecal content of broilers collected at abattoirs and were isolated within the framework of the Swedish Campylobacter control programme. For details on methodology see Materials and methods, resistance in bacteria from animals.
Table 3.7. Distribution of MICs and resistance (%) for Campylobacter jejuni from broilers, 2014. Antimicrobial
Resistance (%)
Distribution (%) of MICs (mg/L)
n=102
≤0.12
0.25
0.5
89.2
2.9
3.9
Ciprofloxacin
4
Erythromycin
0
Gentamicin
0
Nalidixic acid
8
Streptomycin
1
Tetracycline
1
1.0
24.5
71.6
1.0
4.9 99.0
Figure 3.2. Ciprofloxacin and nalidixic acid resistance (%) in Campylobacter jejuni from broilers years 2001, 2002, 2004, 2010, 2012 and 2014. In years 2001-2002 enrofloxacin was tested instead of ciprofloxacin. The number of isolates per year has varied (n=38-102). 25%
15%
10%
Ciprofloxacin/Enrofloxacin
Nalidixic acid
2013
2014
2011
2012
2009
2010
2008
2007
2006
2005
2004
2003
0%
2001
5%
2002
Resistance
20%
1
2
99.0
1.0
4
8
16
1.0
1.0
2.0
17.6
32
64
128
3.9
3.9
>128
2.9 1.0
2.9
70.6
73.5
16.7
2.9
1.0 1.0
Zoonotic aspects on Campylobacter Data for 29 isolates of Campylobacter from humans were available 2014 and of these only five were resistant to either erythromycin or fluoroquinolones. However this is a small number of isolates and in Swedres 2011 (data for 2002-2011) higher resistance percentages were reported for human isolates of Campylobacter spp. for fluoroquinolones (69%), tetra cycline (37%) and erythromycin (7%) than for isolates of C. jejuni from broilers 2014. Notably, resistance to erythromycin, the drug of choice for treatment of human campylobacteriosis, has only been found in two isolates from Swedish broiler meat (Svarm 2013) and never in isolates coming directly from animals in Sweden. It can therefore be concluded that animals in Sweden are an unlikely source for Campylobacter infection with the high resistance levels seen in isolates from humans. Comparisons between data for Campylobacter from animals and humans are hampered because the human isolates are not separated by species or by infections acquired in Sweden or abroad. Campylobacter spp. isolates acquired within the country are expected to have a lower level of resistance.
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Clinical isolates from humans Swedish surveillance of antimicrobial resistance is based on the routine testing of clinical samples in microbiology laboratories. In these laboratories the majority of tests for antibiotic susceptibility are performed using the standardized disk diffusion method. From 2011 and onwards all laboratories are following guidelines and breakpoints proposed by EUCAST for the standardized disk diffusion test (www. eucast.org). Commercially available tests for MIC determination are also used, and in recent years there has also been an increase in the use of automated methods for susceptibility testing and categorization. Two sets of data are included in the surveillance programme. The first set is found under the heading Isolates from blood cultures reported to ECDC/EARS-Net. The data on susceptibility testing of consecutive invasive (blood) isolates are collected from fifteen laboratories in 2014, together representing approximately 80% of the Swedish population. Results on eight important bacterial pathogens are requested by and reported to ECDC. These data form the Swedish part of EARS-Net, the European Antimicrobial Resistance Surveillance Network. As part of the surveillance of bacteria from blood cultures, seven of these Swedish laboratories, with coverage of approximately 48 % of the Swedish population, also deliver data on invasive isolates from all their positive blood cultures. This enables a further insight into clinically important bacterial species other than those reported to ECDC/EARS-Net. These results are presented under the heading Resistance in other bacterial species from blood cultures. The second set of data in the surveillance programme can be described as point-prevalence studies of predefined bacteria and antibiotic combinations in which laboratories are able to report aggregated quantitative data (inhibition zones) via the web-based software ResNet. The methodology is further described in Background data and the results are found under the heading The annual resistance surveillance and quality control programme (ResNet). FIGURE 4.1. Yearly number of bloodstream infections by seven pathogens reported to EARS-Net from Sweden 2007-2014 by participating laboratories. Acinetobacter species was introduced in 2014, but data not shown in figure. 7000 6000 5000 4000 3000 2000 1000 0
2007
2008
2009
2010
2011
Escherichia coli
Klebsiella pneumoniae
Staphylococcus aureus
Streptococcus pneumoniae
Enterococcus faecium
2012
2013
2014
Pseudomonas aeruginosa Enterococcus faecalis
Isolates from blood cultures reported to ECDC/EARS-Net Background In 1998 when EARSS (the European Antimicrobial Resistance Surveillance System) started, two bacterial pathogens were included, Staphylococcus aureus representing hospital-related infections, and Streptococcus pneumoniae representing community-acquired infections. Data on both pathogens was derived from cases with invasive disease (positive blood cultures). After three years the EARSS programme was ready to include new pathogens. The natural choice was to include Escherichia coli, which is by far the most common bacterial pathogen in invasive infections (not counting the normal skin flora bacterial species like CoNS), and also the two enterococcal species E. faecalis and E. faecium. A third step was taken in 2005 when Klebsiella pneumoniae and Pseudomonas aeruginosa were added, and by that time most of the European countries were participating in EARSS. In 2014 Acinetobacter species was added to the programme.
EARSS turned into EARS-Net The transition of the EARSS management from RIVM in the Netherlands to ECDC in Stockholm in 2010 did not change the focus of the surveillance system with regard to bacterial pathogens included, and in Sweden the coordination and validation of results from the participating laboratories is still managed by the Public Health Agency of Sweden, former SMI. A summary of the data reported from Sweden 2007-2014 is presented in Figure 4.1 in which numbers of isolates are shown, and in Table 4.1 where the proportions of resistance to certain antibiotics are included. The numbers of isolates of E. coli and S. aureus were much greater than the numbers for other pathogens, but they also showed increasing trends over the years, whereas the numbers of the other five pathogens were stable. Results and comments
In general the proportions of resistance to clinically important antimicrobials were low, and this has been the typical situation for Sweden and its neighbouring Nordic countries all through the EARSS/EARS-Net history (www.ecdc. europa.eu/en/activities/surveillance/EARS-Net/database/). However, increasing trends of resistance to third-generation cephalosporins are seen for both E. coli and K. pneumoniae. This increase is due to an increasing prevalence of ESBLproducing isolates, whereas the mechanism for resistance to ceftazidime in P. aeruginosa is not ESBL-production (Figure 4.2). In E. coli and K. pneumoniae the levels of cephalosporin resistance has reached 5.4% and 4.0%, respectively (Table 4.1). Resistance to fluoroquinolones is now on a level of approximately 11.7% in E. coli and 5.1% in K. pneumoniae. During 2014 13 participating laboratories reported 59 cases of Acinetobacter species, with resistance to carbapenems at 3.4 % (two cases).
SWEDRES | SVARM 2014
TABLE 4.1. Antimicrobial resistance in isolates from bloodstream infections of eight pathogens included in EARSS/EARS-Net surveillance during the years 2007-2014 2007 Species
Antibiotic
n
Escherichia coli
total no of isolates
3745
Ctx
2.3
%R
4991 2.9
n
%R
5066 3.2
n
%R
5336 4.0
n
2014
%R
6323 4.4
n
n tested % R*
6586 4.9
6576
5.4
0.0
0.0
0.0
0.0
0.0
0.0
6321
0.0
3.3
4.5
5.1
5.5
4.5
6577
6.3
13.3
14.4
13.7
14.0
10.4
9.9
9.9
5170
11.7
6285
2.3
total no of isolates
nd 649
nd 826
nd 755
nd 908
nd 934
nd 933
nd 1028
1009
Ctx
1.4
2.3
1.8
2.3
2.2
2.6
3.1
951
4.0
Imp/Mer Gen/Tob
0.0 1.1
0.0 1.1
0.0 1.0
0.0 2.0
0.0 2.1
0.0 2.1
0.0 2.0
984 1008
0.2 3.2
10.8
12.9
12.2
8.5
5.0
4.6
4.4
766
5.1
964
9.3
total no of isolates Caz
nd 335
total no of isolates Oxa/Fox
total no of isolates
nd 309
nd 326
nd 337
nd 402
nd 350
nd 428
432
4.5
5.2
6.9
5.9
5.2
6.0
6.5
437
5.5
7.1 0
4.0 0
7.7 0
6.7 3.0
7.2 1.0
6.9 1.4
6.3 2.3
432 445
7.6 1.8
10.4
7.6
10.1
10.1
7.0
9.1
7.9
345
7.5
442
5.0
nd 2163
nd 2409
nd 2457
nd 2856
nd 3143
nd 3268
nd 3209
3519
0.5
0.7
1.0
0.5
0.8
0.7
1.2
3511
0.9
0.0
0.0
0.0
0.0
0.0
0.0
0.0
1026
0.0
1028
1213
1060
960
1019
992
861
797
Pen (I+R)
3.0
2.0
3.3
3.8
3.5
5.0
6.6
797
6.3
Ery
5.2
5.2
3.9
3.9
4.5
5.1
5.8
793
6.2
894
0.0
673
15.6
456
0.7
351
22.5
59
3.4
total no of isolates
651
Van
total no of isolates Van Gen (HLAR)
720 0.0
Gen (HLAR)
Acinetobacter species***
4423
n
2013
2.3
Van
Enterococcus faecium
%R
2012
0.0
Fluoroquino lones Ptz**
Enterococcus faecalis
4028
n
2011
2.2
Imp/Mer Gen/Tob
Streptococcus pneumoniae
%R
2010
Imp/Mer
Ptz**
Staphylococcus aureus
n
2009
Gen/Tob
Fluoroquino lones
Pseudomonas aeruginosa
%R
2.3
Fluoroquino lones Ptz** Klebsiella pneumoniae
2008
0.0
16.1 279
718 0.0
20.1 333
776 0.0
18.6 311
824 0.0
15.2 339
779 0.0
16.6 406
851 0.0
14.1 391
912
13.3 431
457
0.0
1.5
0.5
0.3
0.0
0.0
0.0
14.4
24.8
24.1
21.8
22.0
18.4
20.4
total no of isolates Imp/Mer
59 nd
*From 2014 the resistance is expressed as % of isolates tested **Ptz was included from 2014 ***Acinetobacter species was included from 2014
nd
nd
nd
nd
nd
nd
69
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SWEDRES | SVARM 2014
Resistance in other bacterial species from blood cultures
FIGURE 4.2. Proportion of resistance to third generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa. Swedish data in EARSNet 2007-2014, from participating laboratories, covering approximately 80% of the population
Streptococcus pyogenes, Streptococcus agalactiae and Haemophilus influenzae
10
Data on all positive blood cultures were obtained from seven laboratories that are using the same laboratory information system (ADBakt). Their total catchment population is at present 4.7 million, thus representing around 48% of the Swedish population. From these laboratories data on all bacterial pathogens consecutively isolated from blood cultures are retrieved, not only those specified by EARS-Net. In previous SWEDRES reports (2008-2013) data for Streptococcus pyogenes, Streptococcus agalactiae and Haemophilus influenzae were presented, and they are summarized in Table 4.2 together with the most recent data from 2014. Invasive isolates of S. pyogenes (GAS) and H. influenzae are notifiable according to the Communicable Disease Act, but regardless of their antibiotic susceptibility. It is therefore of value to summarise this kind of information in the SWEDRES report. S. agalactiae (GBS) is not included in the Communicable Disease Act, but it is an important pathogen in the context of pregnancy and child birth.
8
6
4
2
0
2007
2008
2009
2010
E. coli, Cefotaxime P. aeruginosa, Ceftazidime
2011
2012
2013
2014
K. pneumoniae, Cefotaxime
Last year was the first year that MRSA exceeded 1%, and the highest level noted for PNSP, at 6.6% I+R, in Sweden ever since the start of EARSS/EARS-Net. This year the number has stabilized at 0.9% MRSA and 6.3% nonsusceptibility to penicillin (I+R) for pneumococci. For the two enterococcal species there were three cases of VRE reported for E.faecium (0.7%), for E.faecalis there is still no report of VRE. High-level aminoglycoside resistance (HLAR) was found in both species at 16-23%, somewhat higher compared to previous years.
TABLE 4.2. Antimicrobial resistance in invasive isolates of Streptococcus pyogenes, Streptococcus agalactiae and Haemophilus influenzae during seven years (2008-2014). 2008 (n=11.115)* Species Streptococcus pyogenes
n Antibiotic (% of tot) Ery
196 (1.8)
Tet Streptococcus agalactiae
Ery
0.5
n (% of tot) 134 (1.2)
14.6 107 (1.0)
Kli
6.5
Amp
63 (0.6)
Ctx
25.4 nd 14.3
%R 2.2
2010 (n=12.296) n (% of tot) 118 (1.0)
9.7 131 (1.1)
6.5
Haemophilus influenzae
Tsu
%R
2009 (n=11.416)
6.9
20.4 nd
1.7
n (% of tot) 188 (1.1)
12.7 166 (1.4)
3.8 49 (0.4)
%R
2011 (n=16.969)
7.8
206 (1.2)
5.4 75 (0.6)
14.3
*Total number of positive blood isolates from participating laboratories **from 2014 the resistance is expressed as % resistance of isolates tested
9.3
76 (0.5)
nd
13.3
%R 3.2
2012 (n=18.117) n (% of tot) 257 (1.4)
%R 2.3
2014 (n=12.609)
2013 (n=18.367) n (% of tot) 297 (1.6)
%R 4.0
13.3
12.5
7.7
6.8
197 (1.1) 13.2
205 (1.1) 12.7
5.8
13.7
9.3
18.4
103 (0.6) 20.4
87 (0.5)
2.5 15.8
1.9 22.3
25 0 17.2
n (% of % tot) n tested R** 149 (1.2)
184 (1.5)
149
2.0
141
7.8
184 13.6 158 10.1
70 (0.6)
61 14.8 58
0.0
70 21.4
SWEDRES | SVARM 2014
The annual resistance surveillance and quality control programme (ResNet) Background
One part of the national surveillance programme on antimicrobial resistance makes use of the web-based software ResNet to receive aggregated data from laboratories and to present them in the form of resistance proportions in their respective geographical areas on a map of Sweden, and also as individual zone histogram graphs as a tool for internal quality assurance. In 2014 six pathogens were included in the program, and the results on these pathogens are presented and analyzed in the following texts and graphs to illustrate trends.
Escherichia coli Escherichia coli, mainly derived from urinary tract infections, have been included in the national surveillance programme regularly since 1996 and every year since 2002. Resistance to commonly prescribed oral antibiotics for treatment of urinary tract infections (UTI) has been tested every year. The number of isolates tested by each laboratory was increased from 100 to 200 from 2006 in order to increase the statistical validity of the data. In 2014, 24 laboratories delivered data as requested. All laboratories used EUCAST methodology, and a total of 6439 isolates were included in the analysis (Figure 4.3). The proportion of resistance for all tested antibiotics were similar between 2013 and 2014 and only slightly increasing for ampicillin, cefadroxil and ciprofloxacin (Figure 4.3). Cefadroxil resistance is used as an indicator for presence of genes coding for ESBLs. It should be noted that ciprofloxacin 5µg is now the recommended disk for detecting fluoroquinolone resistance, and the resistance rate 10,4 % represents resistance (R, not I+R as was the case when nalidixic acid was used) calculated from the zone breakpoint R < 19 mm correlating to the clinical MIC-breakpoint R > 1 mg/L. FIGURE 4.3. Proportion, %, resistant E. coli isolates from urine, 20022014. Resistance (R) to fluoroquinolones was tested by nalidixic acid (screening for I+R) 2002-2011, and by ciprofloxacin from 2011 and onwards. Zone breakpoints relevant at the time of testing were always used. 35 30 25 20 15 10 5 0
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Ampicillin Nitrofurantoin Trimethoprim
Mecillinam Nalidixic acid
Cefadroxil Ciprofloxacin
FIGURE 4.4. Proportion, %, resistant K. pneumoniae isolates from urine, 2005-2014. Resistance (R) to fluoroquinolones was tested by nalidixic acid (screening for I+R) 2005-2011, and by ciprofloxacin from 2011 and onwards. Zone breakpoints relevant at the time of testing were always used. 20
15
10
5
0
2005
2006
2007
2008
2009
2010
2011
Cefadroxil
Mecillinam
Ciprofloxacin
Trimethoprim
2012
2013
2014
Nalidixic acid
Klebsiella pneumoniae K. pneumoniae is an important bacterial species from a hospital infection control point of view. Isolates mainly derived from urine samples have been included in the surveillance programme since 2005. In 2014, 23 laboratories delivered data according to EUCAST methodology, and 2591 isolates were included in the analysis (Figure 4.4). The results indicate that the rates of resistance to all tested antibiotics were the same in 2013 and 2014 except for a slight increase in the resistance to mecillinam.
Pseudomonas aeruginosa Pseudomonas aeruginosa has been included in the surveillance programme on a yearly basis since 2006, with the exception of 2008. Laboratories have been asked to test 100 consecutive isolates of P. aeruginosa with the exclusion of respiratory isolates. In 2014, 22 laboratories delivered data according to EUCAST methodology, and 2480 isolates were included in the analysis (Figure 4.5). Aminoglycoside resistance (gentamicin and/or tobramycin tested) is around 1 %, but with a small increase for gentamicin. Four beta-lactam antibiotics were tested; one cephalosporin, one penicillin-inhibitor combination, and two carbapenems. For all of them, the rates of resistance have been more or less stable since 2010. For the carbapenems, resistance to imipenem continues to be higher (9 %) than to meropenem (5.1 %) in 2014. Resistance to ciprofloxacin show a slight decrease from around 10 % to 8 %.
71
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SWEDRES | SVARM 2014
FIGURE 4.5. Proportion, %, resistant Pseudomonas aeruginosa isolates for four groups of antibiotics tested, 2006-2014 (no data collected in 2008). Zone breakpoints relevant at the time of testing were always used.
FIGURE 4.6. Proportion, %, resistant Staphylococcus aureus isolates from skin and soft tissue infections 2002-2014. In 2005 only results from infections in elderly (> 65 years) patients were reported.
20
10 9 8
15
7 6 5
10
4 3 5
2 1 0
0
2006
2007
2008
2009
2010
2011
2012
Tobramycin Imipenem
Gentamicin Piperacillin-Tazo
2013
2014
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Oxacillin/Cefoxitin Fusidic acid
Ceftazidime Meropenem
Erythromycin Genta/Tobra
Clindamycin Norfloxacin
Ciprofloxacin
Staphylococcus aureus Staphylococcus aureus from skin and soft tissue infections has been included in the annual surveillance programme since 2002. In 2014, 24 laboratories delivered data. All laboratories used the EUCAST methodology, and a total of 5343 isolates were included in the analysis (Figure 4.6). The frequency of MRSA in skin and soft tissue infections (SSTI) (cefoxitin used as test compound) has increased slowly and reached an average value of 1.4% in 2014. The average resistance proportions for erythromycin, clindamycin, fusidic acid and norfloxacin indicates a slight decreasing trend. Resistance to aminoglycosides was still only 1%.
erythromycin, clindamycin (since 2004), tetracycline, trimethoprim-sulfamethoxazole, and norfloxacin (since 2005, used as indicator for fluoroquinolone resistance) using the disk diffusion method. In 2014, 23 laboratories delivered data according to EUCAST methodology, and 2391 isolates were included in the analysis. The national summary of the results, as retrieved from ResNet, are shown in Figure 4.7. During the first 15 years of surveillance there had been a slow increase in the proportions of resistance for all tested antibiotics. In 2010 this successive increase stopped. In 2014 the increase in resistance continued for all tested antibiotics except norfloxacin.
Streptococcus pneumoniae
Haemophilus influenzae
Isolates collected and tested in the surveillance programme were mainly derived from nasopharyngeal cultures. Most of the years a total of approximately 2500 consecutive isolates from all clinical laboratories have been tested for susceptibility to penicillin (by means of oxacillin 1 µg screen disk),
Haemophilus influenzae was re-introduced into the yearly surveillance programme on antibiotic resistance in 2008 after several years with no data collections. In 2014, 24 laboratories delivered data according to the new EUCAST methodology, and 2593 isolates were included in the analysis.
FIGURE 4.7. Proportion, % resistant Streptococcus pneumoniae isolates from respiratory tract specimens 1994-2014. 12 11 10 9 8 7 6 5 4 3 2 1 0
1994
1995
1996
1997
Oxacillin (=Penicillin I+R)
1998
1999
2000
Erythromycin
2001
2002
2003
Clindamycin
2004
2005
2006
Tetracycline
2007
2008
2009
2010
2011
Sulfamethoxazole and trimethoprim
2012
2013
2014
Norfloxacin
SWEDRES | SVARM 2014
FIGURE 4.8. Proportion, %, resistant isolates of Haemophilus influenzae from respiratory tract specimens 1994-2014 (no data collected in 2002-2004, 2006-2007). In 2010-2014 beta-lactamase producing isolates were separated from isolates with other beta-lactam resistance mechanisms by use of penicillin G1 unit disk using the following interpretation: 6 mm = beta-lactamase production, 7-11 mm = other beta-lactam resistance. 35 30 25 20 15 10 5 0
1994
1995
1996
1997
1998
1999
Betalactamase production
2000
2001
2002
2003
Other betalactam resistance
In 2010 methodological changes were introduced (for description see www.nordicast.org) which made results for beta-lactam resistance more difficult to interpret. This was resolved by adjusting the reporting routines. Laboratories were asked to report 6 mm inhibition zones of penicillin G 1 for all beta-lactamase producing isolates, regardless of the actual zone diameter (Figure 4.8). Other mechanisms of betalactam resistance were then assumed if zones of penicillin G 1 unit disk measured 7-11 mm, allowing for a rough estimation of the frequencies of resistance due to other mechanisms of beta-lactam resistance (BLNAR). By doing so the results since 2010 indicate a dramatic increase in BLNAR. However, disk diffusion results must always be verified by MIC determination, and useful interpretation tables for treatment options are issued and updated yearly by NordicAST. In 2013 the high increase in resistance to trimethoprimsulfamethoxazole slowed down. This year, 2014, a high increase in resistance to trimethoprim-sulfamethoxazole was seen again, reaching 30,7 %. The increase in resistance due to BLNAR seen from 2013 continues, while the resistance correlating beta-lactamase production is slightly decreasing. Tetracycline resistance in Haemophilus influenzae was still rare (1.3%) as was resistance to fluoroquinolones (1.4 %), detected by the nalidixic acid screening disk.
Clostridium difficile The Clostridium difficile surveillance programme in Sweden The national surveillance program for Clostridium difficile includes both a voluntary laboratory reporting system of all new cases of C. difficile infection (CDI) and susceptibility testing and epidemiological typing of isolates from the clinical microbiology laboratories. All C. difficile strains isolated during week no. 11 and 39 were sent to the Public Health Agency of Sweden for typing by PCR ribotyping and antibiotic susceptibility testing. Primarily metronidazole and vancomycin resistance was monitored, i.e. the recommended
2004
2005
2006
Tetracycline
2007
2008
2009
2010
Trimethoprim-sulfonamide
2011
2012
2013
2014
Nalidixic acid
treatment choices for CDI. However, since use of antibiotics is a risk factor for acquiring CDI we also tested susceptibility to other antibiotics as an indicator of selective pressure, currently moxifloxacin, clindamycin and erythromycin. All isolates were tested using Etest on Mueller Hinton agar.
Incidence of CDI and distribution of resistant Clostridium difficile isolates in 2014 In 2014, 7691 new CDI cases were reported corresponding to an incidence 79/100,000 inhabitants, indicating that the incidence continues to fall. Also the number of collected isolates from all counties have decreased, from 491 and 458 isolates in 2012 and 2013, respectively, to 412 isolates in 2014. Three isolates in 2014 had a decreased susceptibility against the treatment option metronidazole with MICs of 4 and 2 (n=1 and 2, respectively). These isolates belonged to type 027, responsible for the outbreak in the county of Kronoberg in the beginning of 2014. The proportions of C. difficile isolates resistant to the indicator antibiotics erythromycin and clindamycin increased slightly during 2014 while that of moxifloxacin was the same as in 2013. (Table 4.3). Of particular interest, no resistant isolate of type 046 previously common in the county of Jönköping was detected. Also, the number of type 012 isolates with moxifloxacin resistance, common in the county of Östergötland in 2010-2013, has decreased from 32/34 isolates in 2012 to 10/18 isolates in 2014 (Fig 4.9). Also, both type 017 and 231 showed decreased in numbers in 2014 compared to 2013 but remain clustered to certain regions. Resistant type 027 increased in 2014 due to the outbreak in Kronoberg (http://www.folkhalsomyndigheten. se/documents/statistik-uppfoljning/smittsamma-sjukdomar/ Clostridium-difficile-arsrapporter/Slutrapport-nationellscreening-Clostridium-difficile-typ-027-feb-2014.pdf). Type 078, commonly found also in animals, had variable resistance pattern towards the indicator antibiotics and its proportion has slowly increased from 11/491 (2.2 %) in 2012 to 21/458 (4.6 %) and 22/412 (5.3 %) in 2013 and 2014, respectively.
73
74
SWEDRES | SVARM 2014
TABLE 4.3. Clostridium difficile types resistant to erythromycin, clindamycin and moxifloxacin in Sweden 2014 (n=412). Antimicrobial
Type
% R 2014 (2013)
012
89 (75)
017
100 (79)
027
50 (-)
2
046
0 (53)
1
231
100 (100)
Clindamycin
Erythromycin
Moxifloxacin
Distribution (no. of strains) per MIC (mg/L) <0.008 0.016 0.03
0.06
0.12
0.25
0.5
1
2
4
8
16
1
1
32
64
128
16 8
1
2
1
2 6
Other
13 (7)
1
2
26
45
94
99
32
27
15
4
24
Total
18 (15)
1
2
26
47
97
100
35
28
17
5
54
012
94 (75)
1
14
107
100 (79)
027
67 (-)
2
046
0 (46)
1
231
100 (100)
1
2
8 6 2 1
5
Other
13 (9)
4
40
131
116
37
3
1
4
33
Total
19 (16)
4
40
131
120
39
5
1
6
66
012
55 (63)
3
5
017
75 (59)
1
027
83 (40)
1
046
0 (27)
2
231
100 (100)
10 1
6 5
1 6
Other
9 (6)
7
70
193
66
5
30
Total
14 (14)
7
73
202
68
5
57
The following MIC-breakpoints were used: clindamycin R > 16 mg/L, erythromycin R > 2 mg/L and moxifloxacin R > 4 mg/L.
FIGURE 4.9. Proportion of Clostridium difficile isolates with resistance to moxifloxacin per county 2009-2014.
Moxifloxacin resistance Year2009 2009 0−9 % 10−24 % 25−40 % 41−100 %
256
Year2010 2010
2011 Year 2011
2012 Year 2012
2013 Year 2013
2014 Year 2014
SWEDRES | SVARM 2014
Neisseria gonorrhoeae Notifications according to the Swedish Communicable Diseases Act Gonorrhoea is a notifiable infection and in 2014, 1336 cases (13.7 cases per 100 000 inhabitants) of gonococcal infections were reported to the Public Health Agency of Sweden. Most of these cases were identified in the three largest counties of Sweden, which comprise the cities Stockholm, Gothenburg, and Malmö, respectively. Clinical isolates are in the present report described from the Swedish Reference Laboratory for Pathogenic Neisseria (an external body of the Public Health Agency of Sweden), Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro. In 2014, in total N. gonorrhoeae strains from 382 of the notified cases were fully characterised at this laboratory, representing 29% of the notified cases. Antimicrobial susceptibility testing was performed according to standardized and quality assured methodology using Etest for MIC determination of ceftriaxone, cefixime, azithromycin, spectinomycin, ciprofloxacin, and ampicillin. The used SIR criteria have been determined by The Swedish Reference Group for Antibiotics (SRGA) and The European Committee on Antimicrobial Susceptibility Testing (EUCAST). Produc tion of β-lactamase was examined by nitrocefin discs. The results for 2014 are compared with those from 2007 to 2013 in Table 4.4. Briefly, the levels of resistance to anti-
microbials previously used as first-line treatment for gonorrhoea (penicillins and ciprofloxacin) remain high. The level of resistance to azithromycin also remains high, however, decreased from 13% in 2013 to 9% in 2014. Nevertheless, this decrease might only reflect that only a low number of gonococcal isolates from Stockholm were analyzed at the Swedish Reference Laboratory for Pathogenic Neisseria. The azithromycin resistance has during the recent years been substantially higher in Stockholm, which may reflect an overuse of azithromycin in antimicrobial monotherapy of gonorrhoea and/or other sexually transmitted infections, in particular, urogenital chlamydial infections. In 2014, the resistance to cefixime (2%) continued to decrease and the resistance to ceftriaxone (0.3%) remained low. This is exceedingly promising because ceftriaxone is the last remaining option for empirical antimicrobial monotherapy of gonorrhoea. Similar decreases in the resistance to these extended-spectrum cephalosporins have been indicated in some additional European countries. The reasons for this decline are still unknown, however, most likely the European recommendations to use ceftriaxone (500 mg) plus azithromycin (2 g) in the empiric first-line treatment have been very effective. No gonococcal isolates resistant to spectinomycin has yet been detected in Sweden. However, the availability of spectinomycin is limited (in Sweden as in most countries globally), and it is not suitable for treatment of pharyngeal gonorrhoea.
TABLE 4.4. Proportion of antibiotic resistance (%) and β-lactamase production of Swedish Neisseria gonorrhoeae strains 2007-2014 2007 (n=406)
2008 (n=447)
2009 (n=384)
2010 (n=618)
2011 (n=805)
2012 (n=877)
2013 (n=967)
2014 (n=384)
β-lactamase positive
30
28
44
29
23
23
18
28
Ampicillin
30
28
44
31
24
23
18
28
Cefixime
<1
1
5
6
8
10
4
2
0
<1
0
2
2
1
<1 (0.3)
<1 (0.3)
Ceftriaxone Azithromycin
7
13
6
12
11
10
13
9
Ciprofloxacin
70
63
75
56
55
62
53
60
0
0
0
0
0
0
0
0
Spectinomycin
Neisseria meningitidis Notifications according to the Swedish Communicable Diseases Act Invasive meningococcal disease is a notifiable disease, and in 2014 a total of 49 clinical cases (0.50 cases per 100 000 inhabitants) of the disease were reported. All together 45 clinical invasive isolates from blood, cerebrospinal fluid or puncture (one per patient) were analysed at the Swedish Reference Laboratory for Pathogenic Neisseria (an external body of the Public Health Agency of Sweden), Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital.
Antimicrobial susceptibility testing was performed according to standardized and quality assured methodology using Etest for determinations of MIC values for penicillin G, cefotaxime, meropenem, chloramphenicol, ciprofloxacin and rifampicin. Production of β-lactamase was examined by nitrocefin discs. Ten (22%) isolates had reduced susceptibility to penicillin G (MIC>0.064 mg/L). All isolates (100%) were susceptible to cefotaxime (MIC values of <0.002-0.016 mg/L), meropenem (MICs: 0.003-0.047 mg/L), chloramphenicol (MICs: 0.25-1.5 mg/L), ciprofloxacin (MICs: 0.002-0.006 mg/L), and rifampicin (MICs: 0.003-0.032 mg/L). None of the isolates obtained in 2014 produced β-lactamase, and in fact no β-lactamase-producing meningococcal isolate has ever been found in Sweden.
75
76
SWEDRES | SVARM 2014
Mycobacterium tuberculosis
For 30 of the 522 we have information on previous treatment for TB after 1950 since when effective medication has been available. Out of these 30 cases 26 % (8/30) had some resistance and four were cases of MDR-TB. It is likely that more cases have received treatment earlier but there are no data on this. Of the 15 cases with MDR-TB none was of Swedish origin and the majority (11/15) came to Sweden 2013 or later. In total 11 of the 15 cases had pulmonary manifestations and among them four were smear positive. Genetic typing with MIRU-VNTR (Mycobacterial Interspersed Repetitive Units - Variable Numbers of Tandem Repeat) has been performed on 488 of the 522 isolates so far. This is done to help detect clusters which could indicate ongoing spread in Sweden. Of all 684 reported cases, 67 are considered to have been infected in Sweden. Among culture confirmed cases thought to have been infected in Sweden were the strain is unique, the majority are elderly who most likely were infected in their youth. The proportion of patients with M. tuberculosis resistant against isoniazid has increased slightly in 2014 and we have seen more cases of MDR-TB but no XDR-TB as we did in 2012 and 2013.
During 2014 in total 684 cases of tuberculosis (TB) were reported compared to 655 cases during 2013 which is a small increase. The number and proportion of culture confirmed cases were 527 (77 %) compared to 522 (80 %) in 2013. Myco bacterium tuberculosis was identified in 522 cases and there was one Mycobacterium africanum and four Mycobacterium bovis diagnosed this year. The proportions of cases diagnosed with isoniazid resistant TB in 2014 were 9.8 % (51/522) and MDR 2.9 % (15/522). No XDR-TB were diagnosed during 2014. Isolates of M. tuberculosis resistant to at least one of the four first line drugs (isoniazid, rifampicin, ethambutol or pyrazinamid) were identified in 65 patients corresponding to 12.4% of the 522 with culture confirmed TB, see Table 4.5. As always isoniazid resistance was the most common resistance. Among the cases born in Sweden only two (four %) of 45 with culture confirmed diagnosis had isoniazid-resistant TB and no other resistance was found. As much as 92 % of the TB cases reported in Sweden are born in another country. In this group 13.2 % (63/477) had some kind of resistance and 15 of those 63 had MDR-TB.
TABLE 4.5. Drug resistant tuberculosis in Sweden 2005-2014. Year of diagnosis
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
Culture confirmed M. tuberculosis
448
395
361
434
510
523
473
498
522
522
No
%
No
%
No
%
No
%
No
%
No
%
No
%
No
%
No
%
No
%
Any resistance
52
11.6
43
10.9
49
13.6
57
13.1
58
11.4
68
13
73
15.4
60
12
58
10.7
65
12.4
Isoniazid
46
10.3
38
9.6
46
12.7
51
11.8
51
10
57
10.9
57
12
49
9.8
44
8.4
51
9.8
Rifampicin
5
1.1
6
1.5
15
4.2
15
3.5
14
2.7
20
3.8
19
4
15
3
10
1.9
18
3.4
Ethambutol
3
0.7
1
0.3
7
1.9
6
1.4
7
1.4
12
2.3
10
2.1
12
2.4
8
1.5
15
2.9
Pyrazinamid
6
1.3
6
1.5
11
3
18
4.1
15
2.9
20
3.8
27
5.7
23
4.6
14
2.7
23
4.4
Isoniazid + rifampicin (MDR)
4
0.9
3
0.8
15
4.2
14
3.2
13
2.5
18
3.4
17
3.6
14
2.8
8
1.5
15
2.9
SWEDRES | SVARM 2014
Clinical isolates from animals Isolates tested are from clinical submission of samples to SVA, if not otherwise stated. For many samples, information on the indication for sampling was not available but the vast majority of submissions were likely from animals with diesase. Therefore, data may be biased towards samples from treated animals or from herds where antibiotic treatment is common. Any assessments of trends are based on the assumption that this bias is inherent throughout the observation period. In Svarm, isolates are, when possible, classified as susceptible or resistant by ECOFFs issued by EUCAST (see Guidance for readers for details). This classifies isolates with acquired reduced susceptibility as resistant, which is relevant for monitoring purposes, but it should be understood that this not always implies clinical resistance.
Pigs Escherichia coli
11% since 2001. In 2014, two isolates had MICs above the ECOFF for colistin. This may be true resistance or due to methodological errors, but the isolates were not available for further analyses. Multiresistance occurred in 42% (50/118) of the isolates in 2014 which is higher than previous years (38% in 2013, 24% in 2012, 25% in 2011, 15% in 2010, 19% in 2009 and 14% in 2008). The reason for this increase is uncertain. According to a regulation from 2013, susceptibility testing is generally required before ordination of fluoroquinolones for animals. Due to this, sampling may be biased towards isolates from herds with therapeutic failure with trimethoprimsulphonamides, since fluoroquinolones may be an alternative for treatment of E. coli diarrhoea. Co-resistance between trimethoprim-sulphonamides and other antibiotics is common. The combination of resistance to ampicillin, streptomycin and trimethoprim-sulphametoxazole was the most common trait in 2014, as in previous years, occurring in 64% of the multiresistant isolates. Seventeen percent of all isolates were resistant to four antibiotics. Three isolates were resistant to five antibiotics and one isolate to six antibiotics.
Isolates of Escherichia coli are from clinical submissions of faecal samples or samples taken post mortem from the gastro-intestinal tract. During the latest years, the number of samples submitted has decreased and the sampling strategy has probably changed to some extent. This may influence the proportion of resistant isolates. Some of the isolates are tested by PCR for genes coding for the virulence factors enterotoxin (LT), heat-stable enterotoxin a and b (STa and STb), verocytotoxin (VT2e) and adhesion factors F4, F5, F6, F18 and F41. However, isolates may be susceptibility tested regardless of presence of virulence factors. As in previous years, resistance to ampicillin, streptomycin, tetracycline and trimethoprim-sulphamethoxazole were the most common resistance traits (Table 5.1). Resistance to ampicillin and to trimethoprim-sulphamethoxazole has increased considerably compared to previous years (Figure 5.1). Resistance to enrofloxacin has varied between 6% and
Figure 5.1. Resistance (%) in Escherichia coli from pigs 1992-2014. Clinical isolates from faecal samples or from samples taken post mortem from the gastro-intestinal tract. The number of isolates each year varies (n=74-482). 50%
Resistance
40% 30% 20% 10% 0% 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 Ampicillin
Tetracycline
Trim-sulph.
Table 5.1. Distribution of MICs and resistance (%) in Escherichia coli from pigs 2014. Clinical isolates from faecal samples or from samples taken post mortem from the gastro-intestinal tract. Antibiotic
2014 n=118
a
Distribution (%) of MICs (mg/L)
Resistance (%) ≤0.12
0.25
0.5
1
2
4
48.3
11.9
Ampicillin
40
Cefotaximea
0
100
Ceftiofurb
0
27.5
Colistina
4
Enrofloxacin
11
Florfenicolb
1
5.8
Gentamicin
0
99.2
Neomycin
13
Streptomycin
50
Tetracycline
25
Trim-Sulph.c
46
89.0
3.4
65.2
4.2
16
32
>32
39.8
7.2 81.6
14.3
0.8
2.5
4.1
47.8
64.4 0.8
37.7
7.2
1.4
1.7
11.0
39.0
11.0
11.0
39.0
1.7
25.4
0.8 83.9
53.4
8
8.5
3.4
45.8
49 isolates tested; b 69 isolates tested; c Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim/sulphamethoxazole).
77
78
SWEDRES | SVARM 2014
Brachyspira hyodysenteriae
Actinobacillus pleuropneumoniae
Isolates of Brachyspira hyodysenteriae are from clinical submissions of faecal samples. Analysis of antibiotic susceptibility data from isolates of B. hyodysenteriae from Sweden 19902010 has resulted in a proposal for ECOFFs for the antibiotics tested at SVA (Pringle et al., 2012). In Table 5.2 these ECOFFs are used and historical data have been adjusted. With the new ECOFF >0.25 mg/L for tiamulin, some isolates are classified as resistant. However, with the previously used clinical breakpoint >2 mg/L, no isolate was classified as clinically resistant. The ECOFF for tylosin (>16 mg/L) has not been changed compared to previous years and more than half of the isolates are resistant.
Isolates of Actinobacillus pleuropneumoniae are from post mortem investigations of lungs or from lung samples taken at slaughterhouses within the monitoring programme Svarmpat. The resistance situation is favourable and almost no resistance is detected (Table 5.4). However, since pneumonia caused by A. pleuropneumoniae is an important disease in Swedish pig production, sampling and susceptibility testing is desirable if emerging resistance is to be detected early.
Pasteurella spp. Most isolates of Pasteurella spp. are from post mortem investigations of lungs or from lung samples taken at slaughterhouses within the monitoring programme Svarmpat. Some isolates are also from nasal swabs collected within a control programme for atrophic rhinitis in nucleus and multiplying herds. Isolates from the control programme are likely from healthy pigs, whereas isolates from lung samples are most likely from pigs with respiratory disease. Antibiotic resistance is rare among isolates of Pasteurella spp. (Table 5.5). Isolates from 2013-2014 (n=114) were species identified by MALDI-TOF MS and are Pasteurella multocida. Isolates from earlier years were identified to species with biochemical methods. Most of these isolates are P. multocida, but species identification is in some cases uncertain. However, ECOFFs for P. multocida are used in Table 5.5 for all isolates.
Brachyspira pilosicoli Isolates of Brachyspira pilosicoli are from clinical submissions of faecal samples. ECOFFs for B. pilosicoli are not available for the antibiotics tested. As guide for the choice of antibiotic for treatment of spirochaetal diarrhoea, a clinical breakpoint for tiamulin of >2 mg/L and for tylosin of >16 mg/L are used at SVA. With these breakpoints, 12% of the isolates are resistant to tiamulin and 58% to tylosin (Table 5.3). If the same ECOFF as for B. hyodysenteriae is used, 28% of the isolates are resistant to tiamulin. Tiamulin, valnemulin and tylosin are currently licensed for treatment of spirochaetal diarrhoea in pigs in Sweden and isolates with high MICs of these three substances are present.
Table 5.2. Resistance (%) in Brachyspira hyodysenteriae from pigs 2005-2014 and distribution of MICs for isolates from 2009-2014. Clinical isolates from faecal samples. Antibiotic
d
Distribution (%) of MICs (mg/L)
2007-08 n=38b
2009-14 n=62c
9
3
3
Tiamulin
7
18
6
Tylosin
81
76
58
Tylvalosin
NA
93
56
Valnemulin
0
18
Doxycycline
a
Resistance (%) 2005-06 n=54a
d
≤0.03
0.06
41.9
0.12
0.25
0.5
17.7
67.7
11.3
37.1
14.5
3.2
1.6
3
82.3
17.7
14.5
1
2
4
8
16
24.2
16.1
1.6
11.3
27.4
11.3
32
64
128
>128
1.6
56.5
3.2 3.2
24.2
3.2
3.2
3.2
29 isolates 2005, 25 isolates 2006; b 23 isolates 2007, 15 isolates 2008; c 24 isolates 2009, 9 isolates 2010, 7 isolates 2011, 7 isolates 2012, 8 isolates 2013, 7 isolates 2014; 15 isolates tested; NA=not analysed.
Table 5.3 Distribution of MICs for Brachyspira pilosicoli from pigs 2005-2014, n=289. Clinical isolates from faecal samples. The number of isolates each year varies (n=12-67). Antibiotic
Distribution (%) of MICs (mg/L) ≤0.03
0.06
Doxycycline Tiamulin
33.2
0.12
0.25
0.5
1
2
4
39.1
48.8
4.5
2.8
4.5
0.3
26.3
12.1
8.3
6.2
1.7 5.5
Tylosin Tylvalosin
a
Valnemulin a
126 isolates tested.
45.7
20.1
5.9
8
16
0.7
2.4
9.0
20.4
11.8
0.8
12.7
25.4
25.4
4.8
1.6
9.3
7.3
4.2
2.4
1.4
3.8
32
64
128
>128
4.2
4.5
3.8
5.2
44.6
4.0
13.5
11.9
SWEDRES | SVARM 2014
Table 5.4. Distribution of MICs and resistance (%) in Actinobacillus pleuropneumoniae from pigs 2005-2014. Clinical isolates from post mortem investigations of lungs. The number of isolates each year varies (n=16-57). Antibiotic
Resistance (%) 2005-2014 n=326
0.03
0.06
0.12
0.25
0.5
1
2
4
8
Ampicillin
0
Chloramphenicol
0
Ciprofloxacin
0
Florfenicol
0
Gentamicin
0
0.3
8.9
78.8
Nalidixic acid
0
2.5
60.7
36.8
Penicillin
NRa
Tetracycline
<1
16
32
64
46.9
49.1
1.8
128
>128
100 100 12.6
58.0
29.4 100
0
Streptomycin
Trimethoprim a
Distribution (%) of MICs (mg/L) ≤0.016
0.3
4.9
65.0
29.8 0.3
0
18.7
60.7
12.0
99.7
0.3
2.5
0.9
17.2
1.8
Not relevant since the genus has inherently low susceptibility to streptomycin.
Table 5.5. Distribution of MICs and resistance (%) in Pasteurella spp. from pigs 2005-2014. Clinical isolates from the respiratory tract, isolated from nasal swabs or from post mortem investigations of lungs. The number of isolates each year varies (n=10-95). Antibiotic
Resistance (%) 2005-2014 n=252
Ampicillin
0
Chloramphenicol
0a
Ciprofloxacin
0
Enrofloxacin
0b
Florfenicol
1c
a
Gentamicin
1
Nalidixic acid
0a
Penicillin Streptomycin
Distribution (%) of MICs (mg/L) ≤0.008 0.016
0.03
0.06
0.12
0.25
0.5
1
2
Trim/Sulph
1e
98.8
1.2 4.8
16
32
0.4
0.4
64
128 >128
100 21.6
58.8
0
0
8
100
18.6
1.0 98.7
52.0
1.3
43.3
73.4
21.0
50.5
40.2
8.2
98.4
1.6
0.7
0.7
1.0
4.8
NRd
Tetracycline
4
96.4
3.2
44.4
0.7
1.4
34.1
13.5
4.8
97 isolates tested; b 155 isolates tested; c 248 isolates tested, d Not relevant since the genus has inherently low susceptibility to streptomycin; e 138 isolates tested, concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim/sulphamethoxazole). a
Cattle Escherichia coli from faecal samples Isolates of E. coli are from the gastro-intestinal tract of calves. Most of the isolates are probably from calves no more than a few weeks old, i.e. during a period when resistance in enteric bacteria often is high in cattle. However, in the isolates from the period 2012-2014 resistance was higher than previous years for ampicillin, streptomycin and tetracycline (Table 5.6). Multiresistance occurred in 76% (22/29) of the isolates from 2014, compared to 70% in 2013, 50% in 2012 and 40% in 2007-2011. The reason for the observed increase is not known. However, a biased material, due to sampling in herds with therapeutic failure and to new legislation that states susceptibility testing, could have influenced the results.
Moreover, the low number of tested strains in 2014 makes it difficult to draw conclusions on trends. In 2012, there were differences in resistance between isolates from samples investigated at SVA and samples from a regional laboratory in the southern part of Sweden. The reason for the differences is not known, but geographical origin, type of herds and indication for sampling may influence differences in resistance. Two isolates from 2010, one from 2012 and one from 2013 had a MIC of ceftiofur above the ECOFF. The isolates from 2010 and 2013 were not available for further investigation but since the MIC was just above the cut-off value, the results are probably due to methodological errors or the isolates express chromosomal AmpC. The isolate from 2012 had an AmpC phenotype, but no gene was detected with PCR.
79
80
SWEDRES | SVARM 2014
Escherichia coli from milk samples
19% (18/95) of all isolates. Resistance to ampicillin, streptomycin and trimethoprim-sulphamethoxazole were the most common traits and 16% of all isolates were resistant to all three of these antibiotics. Three isolates were resistant to five antibiotics (ampicillin, enrofloxacin, streptomycin, tetracycline and trimethoprim-sulphamethoxazole).
Isolates of E. coli are from clinical submissions of milk samples from dairy cows. It is probable that most sampled cows had clinical mastitis. According to a regulation from 2013, susceptibility testing is generally required before ordination of fluoroquinolones for use in animals. As a consequence of this the number of isolates of E. coli from milk samples that are susceptibility tested has increased considerably during 2013 and 2014 compared to previous years. Although antibiotic treatment is not always indicated for E. coli mastitis, fluoroquinolones may be the clinically most effective group of antibiotics if treatment is required. In the material from 2014, 32% (30/95) of the isolates were resistant to at least one antibiotic. Resistance to ampicillin, streptomycin, tetracycline or trimethoprimsulphamethoxazole was most common and has increased compared to 2013 (Table 5.7). Multiresistance occurred in
Klebsiella pneumoniae from milk samples Isolates of Klebsiella pneumoniae are from clinical submissions of milk samples from dairy cows. Resistance was uncommon and 74% of isolates was susceptible to all tested antibiotics, excluding ampicillin, and MICs were in accordance with the results from susceptibility testing of isolates from 2002-2003 (Bengtsson et al., 2009). Resistance to streptomycin was the most common resistance trait. Multiresistance did not occur in isolates from 2014.
Table 5.6. Resistance (%) in Escherichia coli from cattle 1992-2002 and 2005-2014. Distribution of MICs for isolates from 2012-2014. Clinical isolates from faecal samples or from samples taken post mortem from the gastro-intestinal tract. Antibiotic
Resistance (%)
Distribution (%) of MICs (mg/L)
1992-02
2005-06
2007-11
2012-14
n=220
n=63
n=70
n=117
Ampicillin
24
32
33
55
Ceftiofur
0
0
3
2
Enrofloxacinb
10
13
10
12
Florfenicol
0g
0
1
0
a
g
Gentamicin
5
0
1
1
Neomycin
8
13
24
19
Streptomycind
42
54
49
77
c
Tetracycline
31
49
64
77
Trim/Sulph.e,f
11
21
17
21
0.25
≤0.12
88.0
0.5
1
2
4
8
16
38.5
6.0
0.9
54.7
34.2
64.9
0.9
4.5
83.8
9.9
1.8
3.4
0.9
0.9
6.8
86.3
12.8
20.5
15.4
1.7
1.7
15.4
17.9
5.1
1.7
75.2
2.6
0.9
>32
0.9
65.8
77.8
32
76.9
0.9
20.5
Cut-off value >2 mg/L until 2006; b Cut-off value >0.25 mg/L until 2004; c Cut-off value >8 mg/L until 2001; d Cut-off value >32 mg/L until 2006; e Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim/sulphamethoxazole); f Cut-off value >4 mg/L until 2006; g 16 isolates tested.
a
Table 5.7. Resistance (%) in Escherichia coli from dairy cows 2013-2014 and distributions of MICs for isolates from 2014. Clinical isolates from milk. Antibiotic
a
Distribution (%) of MICs (mg/L)
Resistance (%) 2013 n=142
2014 n=95
Ampicillin
14
20
Ceftiofur
1
0
Enrofloxacin
5
6
Florfenicol
0
Gentamicin
0
Neomycin
4
1
1
2
4
8
16
5.3
44.2
28.4
2.1
20.0
0
1.1
47.4
49.5
2.1
0
95.8
4.2 94.7
4.2
1.1
3.2
32.6
38.9
18.9
2.1
18.9
Streptomycin
16
25
Tetracycline
9
19
Trim-Sulph.a
11
17
≤0.12
93.7
0.25
0.5
9.5
68.4
22.1
1.1
4.2
1.1
8.4 83.2
Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim/sulphametoxazole)
51.6
16.9
32
>32
3.2
22.1
SWEDRES | SVARM 2014
Staphylococcus aureus from milk samples Isolates of Staphylococcus aureus are from milk samples from dairy cows with clinical mastitis. Samples were submitted within a field study in which participating veterinary practices sent in milk samples from dairy cows with clinical mastitis in a randomized way. Resistance was uncommon in this material and in accordance with the results from susceptibility testing of isolates from 2002-2003 (Bengtsson et al., 2009). Since 2002-2003, the proportion of beta-lactamase producing isolates has decreased from 7% to 1%. In order to reduce transmission of betalactamase producing S. aureus among Swedish dairy cows, it
is recommended not to keep animals with mastitis caused by such bacteria in the herd. The decrease in beta-lactamase producing S. aureus over the last decade indicates that this strategy has been effective. However, the sampling strategy and number of sampled cows are not similar in the two studies, and conclusions on trends should therefore be drawn with caution. For four of the isolates, MICs of oxacillin were above the cut-off value. Three of the isolates had MIC 2 mg/L and one isolate had MIC 1 mg/L (Table 5.9). These four isolates were tested for the presence of mecA and mecC genes with PCR but the genes were not detected.
Table 5.8. Resistance (%) in Klebsiella pneumoniae from dairy cows 2013-2014 and distributions of MICs for isolates from 2014. Clinical isolates from milk. Antibiotic
a
Distribution (%) of MICs (mg/L)
Resistance (%) 2013 n=41
2014 n=39
≤0.12
0.25
0.5
1
2
7.7
82.1
10.3
7.7
2.6
Ampicillin
NR
NR
Ceftiofur
0
0
Enrofloxacin
0
3
Florfenicol
2
3
2.6
Gentamicin
0
0
100
b
4
8
16
32
>32
100
b
89.7
43.6
Neomycin
2
0
100
Streptomycin
7
18
71.8
Tetracycline
15
5
Trim-Sulph.a
5
0
5.1
71.8
46.2
5.1
2.6
10.3
17.9
5.1
12.8
5.1
100
Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim/sulphamethoxazole); b Not relevant as the genus is inherently resistant to ampicillin.
Table 5.9. Distribution of MICs and resistance (%) in Staphylococcus aureus isolated from dairy cows in 2013-2014. Clinical isolates from milk. Antibiotic
Resistance (%) 2013-2014 n=74
a
Distribution (%) of MICs (mg/L) ≤0.016
0.03
0.06
0.12
0.25
0.5
9.5
45.9
43.2
12.2
52.7
33.8
98.6
1.4
1
2
Cephalothin
0
Ciprofloxacin
0
Chloramphenicol
0
Clindamycin
1
Erythromycin
0
Fucidic acid
8
Gentamicin
0
Kanamycin
0
Oxacillin
5
Penicillina
1
Tetracycline
1
93.2
5.4
1.4
Trimethoprim
9
5.4
41.9
43.2
Denotes beta-lactamase production.
17.6
17.6
5.4
4
8
16
5.4
91.9
2.7
8.1
1.4 1.4
32.4
50.0
12.2
44.6
6.8
1.4
89.2
8.1
2.7
5.4
13.5
56.8
16.2
17.6
18.9
4.1
1.4
52.7
17.6
8.1
1.4
32
64
128
>128
81
82
SWEDRES | SVARM 2014
Table 5.10. Distribution of MICs and resistance (%) in Pasteurella spp. from calves 2005-2014. Clinical isolates from the respiratory tract, isolated from nasal swabs or from post mortem investigations of lungs. Antibiotic
Resistance (%) 2005-2014 n=293
a
Ampicillin
0
Enrofloxacin
0
Florfenicol
0
Penicillin
0
Tetracycline
0
Trim/Sulph.a
0
Distribution (%) of MICs (mg/L) ≤0.06
0.12
0.25
0.5
1
2
4
8
16
>16
100
b
96.6
3.4
53.9
38.9
100 7.1 95.9
4.1
1.7
1.0
96.9
0.3
Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim/sulphamethoxazole); 268 isolates tested. b
Pasteurella spp. Isolates of Pasteurella spp. are from nasal swabs from calves with respiratory disease or from post mortem investigations of lungs. Isolates from 2013-2014 were species identified by MALDI-TOF MS and are Pasteurella multocida. Isolates from earlier years were species identified with biochemical methods. Most of these isolates are also P. multocida, but species identification is in some cases uncertain. However, ECOFFs for P. multocida are used, if possible, in Table 5.10 for all isolates. Antibiotic resistance was rare among isolates of Pasteurella spp. (Table 5.10) and penicillin is considered the substance of choice for treatment of pneumonia in calves in Sweden. Isolates of beta-lactamase producing Pasteurella spp. have
been confirmed in one herd in 2003 and beta-lactamase producing Mannheimia haemolytica in one herd in 2010.
Sheep Mannheimia haemolytica and Bibersteinia trehalosi Isolates of Mannheimia haemolytica and Bibersteinia trehalosi are from post mortem investigation of lungs. Resistance was uncommon in this material (Table 5.11). Since ECOFFs are rarely available for these bacteria, ECOFFs for P. multocida are used, when possible. Two isolates had MICs just above the ECOFF for penicillin, but these isolates were not available for further analyses.
Table 5.11. Distribution of MICs and resistance (%) in Mannheimia haemolytica and Bibersteinia trehalosi from sheep 2013-2014. Clinical isolates from the respiratory tract, isolated from post mortem investigations of lungs. Antibiotic
Resistance (%) 2013-2014 n=44
a
Ampicillin
0
Enrofloxacin
5
Florfenicol
0
Penicillin
5
Tetracycline
0
Trim/Sulph.
0
a
Distribution (%) of MICs (mg/L) ≤0.06
0.12
0.25
0.5
1
79.5
15.9
2.3
2.3
61.4
18.2
15.9
4.5
2
100
100
95.5 97.7
Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim/sulphamethoxazole).
4.5 2.3
4
8
16
>16
SWEDRES | SVARM 2014
83
Antibiotic resistant E. coli that has been selected for in the farm animal population may be transmitted to humans via the food-chain (van den Bogaard and Stobberingh, 2000). Of special concern is E. coli that has acquired resistance to fluoroquinolones or ESCs, which are critically important antibiotics in human medicine (WHO, 2012). Faecal E. coli from preweaned calves is often multiply resistant, even without exposure to antibiotics (Swedres-Svarm, 2013; de Verdier et al., 2012). To increase the knowledge about risk factors for the occurrence and dissemination of faecal resistant E. coli from calves and to define measures to reduce the occurrence, a PhD project was initiated in 2011. Below is a summary of the studies included in the project. The full thesis “Antimicrobial resistant Escherichia coli in faeces of preweaned dairy calves” is available from http://pub.epsilon.slu.se/. In a study on 243 farms risk factors for resistant E. coli were sought (Duse et al., 2015). Increasing calf age was a consistent protective factor against resistant E. coli, with the prevalence being highest around one week of age and then gradually declining. The microbiota of the gastrointestinal tract of the new-born calf is less diverse than in older cattle (Mayer et al., 2012). Many resistant E. coli strains carry factors that enhance their colonization ability (de Lastours et al., 2014; de Verdier et al., 2012) and competitiveness against susceptible E. coli (Eberhart et al., 2014), which may explain their successful establishement in the young calf gut. The decline in resistant E. coli with increasing age may be due to a combination of acquired immunity to certain strains (Runnels et al., 1980) and increased competition from an increasingly diverse gastrointestinal microbiota (Mayer et al., 2012). Feeding colostrum from cows treated with antibiotics at drying off did not affect the shedding of antibiotic resistant E. coli by calves. In contrast, feeding milk from cows treated with antibiotics during lactation to calves increased faecal streptomycin resistant E. coli and quinolone resistant E. coli (QREC). It can be assumed that antibiotics in milk inhibit susceptible species in the gastrointensitnal tract, and thus, disturbs the composition of the microbiota. A disturbed gastrointenstintal microbiota is tantamount to reduced colonization resistance which may ease the establishment of antibiotic resistant E. coli. Hence, feeding milk from antibiotic-treated cows cannot be recommended from a resistance point of view. Treatment with broad-spectrum antibiotics in both cows and calves increased the occurrence of faecal E. coli with resistance to related or unrelated drugs (Duse et al., 2015). Treatment of cows may result in selection of
resistant E. coli in their gastrointestinal microbiota, which could readily be spread by faeces in the farm environment and transferred to calves. Hence, prudent use of antibiotics likely reduces the overall burden of resistant E. coli on dairy farms and should include not only treatment of calves, but also treatment of cows. Resistant E. coli was also more common on large than on small farms, which is a concern with the current development towards larger farms in Sweden. Calves on farms with parlour milking compared to farms with tie stall milking or automatic milking systems, and calves on farms in South and East compared to North Sweden were also more likely to carry resistant E. coli. The latter may be due to clonal dissemination of resistant E. coli between closely located farms. The prevalence of faecal QREC from calves varied substantially between farms, and this prompted additional studies on risk factors and within-farm dissemination of QREC (Duse et al. 2015). On farms with high prevalence of faecal QREC in calves, QREC was also frequently found in calf feed, water and milk troughs, in the calving pen and in faecal samples from newly calved cows.Thus, it was assumed that QREC is maintained in the calf group by faecal-oral circulation through contamination of feed, water and milk troughs and that transit of cows and calves via the calving area may be important for the dissemination of QREC between cows and calves. On most farms, two to four genotypes were found throughout the farm, indicating within-farm clonal dissemination of QREC. Poor farm hygiene, group calving and infrequent use of the calving pen as a sick pen were risk factors for faecal QREC in cows and calves. Measures to reduce the burden of QREC on farms may be related to factors that decrease contamination and spread of faecal material, such as proper cleaning of feed, water and milk troughs as well as the use of single calving pens. The same clone of QREC was also found on more than one farm, suggesting clonal spread between farms. Farms that were located closer to each other were more likely to share the same QREC clone, possibly due to an epidemiological connection between those farms. Quinolone resistant E. coli was also more common on farms that purchase cattle or share animal transporter with other farmers. A positive correlation was also found between the number of purchased cattle and the genetic diversity of QREC within the farm, suggesting that new QREC genotypes are introduced to the farm via purchase of cattle. These results indicate that QREC is spread between farms via the movement of cattle and equipment.
In focus
Risk factors for antibiotic resistant Escherichia coli in faeces of preweaned dairy calves
84
SWEDRES | SVARM 2014
Farmed fish
At present there are only published interpretative criteria for MIC data for A. salmonicida from aquatic animals (CLSI, 2014b). Epidemiological cut-offs of >4 mg/L and >1 mg/L was proposed by CLSI for florfenicol and oxytetracycline, respectively. Using those criteria, one isolate is interpreted as resistant to florfenicol and two to tetracycline. A bimodal distribution with deviating high MICs of the quinolone nalidixic acid indicate the presence of acquired resistance to this antibiotic as well. Recently, Smith et al. (2014) proposed ECOFFs for florfenicol, oxolinic acid and oxytetracycline for F. psycrophilum. These are used in the distributions in Table 5.13. Resistance to oxolinic acid and oxyteracycline was high in this material. There is a limited therapeutic use of the quinolone oxolinic acid as well as of tetracycline in aquaculture in Sweden.
Isolates presented are from clinical submissions of farmed fish. In 2014, data for nine isolates of Aeromonas salmonicida subsp. achromogenes and nine of Flavobacterium columnare were available. Data for 2009-2014 are compiled and presented as distributions of MICs in Table 5.12. In Table 5.13 MIC distributions for isolates of Flavobacterium psycrophilum are presented. Isolates of F. psychrophilum are from 22 disease outbreaks. In all but six of these samplings more than one isolate of F. psychrophilum were susceptibility tested. Most isolates of A. salmonicida and F. columnare are from brown trout or archtic char whereas most isolates of F. psychrophilum are from rainbow trout.
Table 5.12. Distribution of MICs for Aeromonas salmonicida subsp. achromogenes (n=69) and Flavobacterium columnare (n=40) from farmed fish 2009-2014. Bacterial species
Antibiotic
Resistance (%) 2009-2014
Florfenicol Aeromonas salmonicida subsp. achromogenes
Distribution (%) of MICs (mg/L) ≤0.5
1
1
Nalidixic acida Tetracycline
3
81.7
1.7
94.2
2.9
Florfenicol Flavobacterium columnare
a
2
4
97.1
1.4
8
16
32
64
>64
1.7
6.7
8.3
1.4
1.4
1.4
100
Nalidixic acidb
77.4
12.9
Tetracycline
97.5
2.5
3.2
3.2
3.2
60 isolates tested; b 31 isolates tested.
Table 5.13. Distributions of MICs and resistance (%) in Flavobacterium psycrophilum from farmed fish 2014. Antibiotic
Resistance (%) 2014 n=61
a
Florfenicol
0
Oxolinic acid
69
Oxytetracycline
80
Trim/Sulph.a
87
Distribution (%) of MICs (mg/L) ≤0.008
0.016
0.03
3.3
0.06
0.12
3.3
26.2
1.6 1.6
8.2
3.3
16.4 1.6
Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim/sulphamethoxazole).
0.25
0.5
1
2
4
8
26.2
29.5
36.1
8.2
8.2
60.7
8.2
23.0
13.1
23.0
19.7
18
9.8
26.2
24.6
>8
SWEDRES | SVARM 2014
85
Svarmpat – monitoring of resistance in pathogens from farm animals
Selected studies within Svarmpat in 2014: Milk samples in dairy cows
• Screening for MRSA in milk samples from dairy cows started in 2010 and is still ongoing. Selected isolates of beta-lactamase producing Staphylococcus aureus from routine submissions to SVA are investigated for methicillin-resistance. During 2010-2014, 702 isolates were tested and MRSA with mecC was confirmed in 3 isolates from 2010, 1 from 2011 and 1 from 2013, and MRSA with mecA was confirmed in 1 isolate from 2012 and 1 from 2014. In addition, 513 isolates of S. aureus without beta-lactamase production was tested in 2013, but MRSA was not detected. See Notifiable diseases, MRSA in animals. • Continuous monitoring of bacterial findings in clinical mastitis in dairy cows started in 2013. Randomly collected milk samples from dairy cows with clinical mastitis are cultured and isolated bacteria are susceptibility tested. Mastitis is an important disease in dairy cows. Most bacteria causing mastsitis in dairy cows in Sweden are sensitive to penicillin and penicillin is the drug of choice for treatment if antibiotic is needed. It is, however, desirable to continuously monitor the situation concerning bacterial panorama and resistance situation. Resistance in S. aureus isolated in this study is presented in Clinical isolates from animals.
Respiratory tract samples in pigs, cattle and sheep
• Resistance in Actinobacillus pleuropneumoniae and Pasteu rella multocida from pigs, P. multocida and Mannheimia haemolytica from cattle and M. haemolytica and Bibersteinia trehalosi from sheep are continously susceptibility tested within Svarmpat. Resistance to penicillin in these bacteria is very uncommon, supporting the recommendation to primarily use penicillin for treatment of pneumonia in pigs, cattle and sheep. For resistance results see Clinical isolates from animals. Enteric samples from pigs
• Swine dysentery and spirochaetal diarrhoea in pigs are important diseases in many countries. The resistance situation in the causative agents, Brachyspira hyodysenteriae and Brachyspira pilosicoli, in Sweden is favourable compared to other countries. Within Svarmpat, isolates from all identified herds with these diseases in Sweden are susceptibility tested. For resistance results see Clinical isolates from animals. Enteric and environmental samples from broilers
• The occurrence of ESBL-producing E. coli in broilers, laying hens and turkeys are monitored and the epidemiology of this resistance is studied in several projects and the work is party financed by Svarmpat. See Notifiable diseases, ESBL-producing Enterobacteriaceae.
Questionnaire about specified pig diseases During 2014, a questionnaire about the disease syndromes head tilt and exudative epidermitis in pigs was performed with the aim to increase knowledge about occurrence and outcome of treatment. Answers were received from 186 pig veterinarians, pig farmers and pig farm workers. Results are being compiled.
In focus
The Svarmpat programme (Swedish Veterinary Antibiotic Resistance Monitoring – farm animal pathogens) is a project in co-operation between Farm & Animal Health and SVA that started in 2005. It is financed by the Swedish Board of Agriculture. The purpose of Svarmpat is to reduce emergence and spread of antibiotic resistance in pathogenic bacteria from farm animals. The work is performed by monitoring and documenting antibiotic resistance, by activities that increase knowledge of antibiotic resistance and prudent use of antibiotics, and by communication of knowledge generated within the programme to practitioners and farmers.
SWEDRES | SVARM 2014
Horses
Figure 5.2. Resistance (%) in clinical isolates of Escherichia coli from the genital tract of mares 2004-2014. The number of isolates each year varies (n=124-273).
Escherichia coli Isolates of Escherichia coli are from clinical sampling of the genital tract of mares. As in previous years, resistance to trimethoprim-sulphametoxazole and streptomycin was most common in 2014 (Table 5.14). Since 2004, the rate of resistance has differed somewhat between the years, but the figures seem to decline (Figure 5.2). Multiresistance was detected in 5 % (12/229) of the isolates, which is comparable to the figures in 2013 (4%) and 2012 (6%), but less than 2011 (11%). Ten of the isolates were resistant to three substances and one to four substances, including ampicillin, trimethoprim-sulphametoxazole and/ or different aminoglycosides, but also to tetracycline and enrofloxacin. However, no dominant trait was oserved. One isolate was resistant to six substances; ampicillin, enrofloxacin, gentamicin, neomycin, streptomycin, tetracycline and trimethoprim-sulphametoxazole. No ESC resistant E. coli was isolated from this material. For more information of ESBL in horses, see ESBLproducing Enterobacteriaceae in animals.
30% 25% 20% Resistance
86
15% 10% 5% 0% 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Gentamicin
Ampicillin Streptomycin
Trim-Sulph.
Table 5.14. Distributions of MICs and resistance (%) in Escherichia coli from horses in 2014. Clinical isolates from the genital tract of mares. Antibiotic
Resistance (%) 2014 n=229 b
Ampicillin
7
Cefotaxime
0
Colistin
4
Enrofloxacin
2
Gentamicin
1
Neomycin
1
Streptomycin
10
Tetracycline
3
Trim-Sulph.a
12
Distribution (%) of MICs (mg/L) ≤0.12
0.25
0.5
1
2
4
8
16
44.1
48.5
0.9
6.6
28.9
2.8
0.5
0.5
0.4
0.4
32
64
100 67.4 98.3
1.3
0.4 98.3
0.9
98.7
91.7 88.2
4.8
1.3 72.1
18.0
0.4
3.1
0.4
9.6
11.8
Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim-sulphametoxazole); n=229 for all substances except cefotaxime and colistin with 218 tested isolates respectively.
a
b
Table 5.15. Distribution of MICs and resistance (%) in Streptococcus zooepidemicus isolated from horses in 2014. Clinical isolates from the respiratory tract. Antibiotic
Ampicillin Enrofloxacin Florfenicol Gentamicin
Resistance (%) 2014 n=129
Distribution (%) of MICs (mg/L) ≤0.12
0.25
0.8
0.8
0.5
0
1
53.5
0 NR 0
Spiramycin
0
Tetracycline
2
Trim-Sulph.a
5
4
8
16
32
45.0
47.3
5.4
100
NR b
Penicillin
2
b
45.0 98.4
1.6
0.8
1.6
100 100
82.2
41.9
47.3
10.1
3.1
9,3
1.6 4.7
Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim-sulphametoxazole); b NR= Not relevant as the inherent susceptibility is above concentrations that can be obtained during therapy.
a
>32
SWEDRES | SVARM 2014
Table 5.16. Distribution of MICs and resistance (%) in Staphylococcus aureus from horses 2014. Clinical isolates from the skin. Antibiotic
Resistance (%) 2014
Distribution (%) of MICs (mg/L) ≤0.12
0.25
0.5
1
2
36.4
4
8
16
1.5
2.3
77.2
18.9
55.3
5.3
2.3
0.8 3.0
65.9
28.8
2.3
97.8
0.8
1.5
32
>32
n=132 Ceftiofur
0
Enrofloxacin
3
Florfenicol
2
Gentamicin
2
Oxacillin
0
Penicillina
18
Spiramycin
<1
15.2
75.0
9,1
7
24.2
47.0
22.0
0.8
1.5
Streptomycin
a
100
Tetracycline
3
Trim-Sulph.b
<1
97.0 99.2
0.8
0.8 3.8
3.0
0.8
Denotes beta-lactamase production; b Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim-sulphametoxazole).
Figure 5.3. Resistance (%) in clinical isolates of Staphylococcus aureus from skin of horses 2007-2014. The number of isolates each year varies (n=96-145). 40% 35%
Resistance
30% 25% 20% 15% 10% 5% 0% 2007
2008
2009
2010
Penicillin Streptomycin
2011
2012
2013
2014
Gentamicin Trim-Sulph.
Staphylococcus aureus Isolates of Staphylococcus aureus are from clinical sampling of skin, excluding wounds and abscesses. Table 5.16 presents the distribution of MICs and resistance in isolates from 2014. Levels of resistance for gentamicin, penicillin, streptomycin and trimethoprim-sulphametoxazole over the last eight years are shown in Figure 5.3. Resistance to penicillin due to betalactamase production dominates. After a peak in 2008-2009 (36%), the figures have stabilised around 20% for the last five years. No MRSA was detected in this material. For more information on MRSA isolated from horses, see Notifiable diseases, MRSA in animals.
Dogs Escherichia coli
Streptococcus zooepidemicus Isolates of Streptococcus zooepidemicus are from clinical sampling of the respiratory tract. Resistance to antibiotics was rare in 2014 (Table 5.15 ). Over the years studied in Svarm, the susceptibility to penicillin and ampicillin has remained stable. Resistance to the other antibiotics tested has been rare from 1995 up to date (historical data not shown), except for trimethoprim-sulphametoxazole with gradually declining resistance rates and tetracycline with an unexplained peak of 7% resistance in 2010. Streptococcus zooepidemicus have a low inherent susceptibility to fluoroquinolones (e.g. enrofloxacin) and aminoglycosides (e.g. gentamicin). The MICs of these antibiotics were high and above concentrations obtained during systemic therapy.
Isolates of Escherichia coli are from clinical sampling of urine, submitted either as urine or cultures on dip-slides or other agar plates. As in previous years, resistance to ampicillin was the most common trait in 2014 (Table 5.17). Levels of resistance to ampicillin, enrofloxacin and trimethoprim-sulphametoxazole have been slightly declining since 2005 (Figure 5.4). Multiresistance was detected in 2% (20/943) of the isolates. This is about the same figure as in 2013 (3%) and halved compared to 2011-2012. Fourteen of the twenty multiresistant isolates were resistant to three substances and six to four substances. Of the multiresistant isolates were 19 resistant to ampicillin, 15 to trimethoprim-sulphametoxazole, 12 to enrofloxacin and 11 to tetracycline. Furthermore four of those strains were resistant to one or more of cefotaxime, colistin, gentamicin and/or nitrofurantoin, but no specific phenotype stood out.
87
SWEDRES | SVARM 2014
Six of seven E. coli isolates resistant to cefotaxime were further analysed for ESBL-production. Genes conferring transmissible ESBL or AmpC resistance were found in four of these isolates. For more information, see ESBL-producing Enterobacteriaceae in animals.
Figure 5.4. Resistance (%) in clinical isolates of Escherichia coli from urine of dogs, 2005-2014. The number of isolates each year varies (n=304-943). 25%
20%
Staphylococcus pseudintermedius Isolates of Staphylococcus pseudintermedius are from clinical sampling of skin, excluding wounds and abscesses. Occurrence of penicillin resistance due to beta-lactamase production was constantly high, 77% in 2014 and during the presented 15 years between 75 and 90% (Table 5.18 and Figure 5.5). Occurrence of resistance to clindamycin, erythromycin, fusidic acid and/or tetracycline fluctuate slightly between the years, but remains at approximately the same levels since 2004 (Figure 5.5). Multiresistance is common in S. pseudintermedius, between 2009 and 2013 the figures have varied between 26 and 36%, and was in 2014, 34 % (173/513). Resistance to five or more antibiotics was observed in one fourth (44/173) of the multi resistant isolates (of all isolates 9%). The most common multi resistant phenotype was resistance to penicillin, clindamycin
Resistance
88
15%
10%
5%
0% 2006
2007
2008
2009
2010
2011
Ampicillin Nitrofurantoin
2012
2013
2014
Enrofloxacin Trim-Sulph.
Table 5.17. Distribution of MICs and resistance (%) in Escherichia coli from dogs 2014. Clinical isolates from urine. Antibiotic
a
Resistance (%) 2014 n=943 b
Ampicillin
13
Cefotaxime
<1
Colistin
5
Enrofloxacin
7
Gentamicin
<1
Nitrofurantoin
<1
Tetracycline
5
Trim-Sulph.a
5
Distribution (%) of MICs (mg/L) ≤0.12
0.25
0.5
99.3
93.2
2.3
2.4
1
2
4
8
16
51.4
33..6
1.7
13.3
2.6
0.6
1.3
0.2
0.5
72.6
22.9
1.0
0.1 98.7
93.8
0.7
>32
1.0 1.0
0.1
0.2 97.6
87.2
32
6.7
0.2
1.5
1.7
0.7
4.7
5.2
Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim-sulphametoxazole); b n=943 for all substances, except colistin with 690 tested isolates.
Table 5.18. Distribution of MICs and resistance (%) in Staphylococcus pseudintermedius isolated from clinical submissions of skin samples in dogs 2014. Antibiotic
Distribution (%) of MICs (mg/L) ≤0.12
0.25
0.5
1
2
4
8
78.2
0.2
21.6
1.2
0.4
0.8
Cephalothin
<1
Clindamycin
22
Enrofloxacin
2
Erythromycin
23
0.2
22.6
Fusidic acid
20
76.8
3.8
19.5
Gentamicin
2
97.1
0.8
1.8
Nitrofurantoin
0
Oxacillin
<1
Penicillin
77
Tetracycline
23
Trim-Sulph.b
4
a
a
Resistance (%) 2014 n=513
99.8
68.4
27.1
5.2 77.2
99.6
0.2
0.2
99.6
0.4
0.4
13.3
23.0 0.8
32
0.2
77.0 82.1
16
0.2
3.7
Denotes beta-lactamase production; b Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim/sulphamethoxazole).
>32
SWEDRES | SVARM 2014
and erythromycin in 15% (25/173) of all multiresistant isolates. This phenotype was present in 37% (65/173) of the isolates resistant also to four or more substances, most commonly combined with resistance to enrofloxacin, fusidic acid and/or tetracycline. One MRSP isolate was found in this material. For more information on MRSP isolated from dogs, see Notifiable diseases, MRSP in animals.
Figure 5.5. Resistance (%) in clinical isolates of Staphylococcus pseudintermedius from skin of dogs 2004-2014. The number of isolates each year varies (n=89-566). 100% 90% 80% Resistance
70%
Staphylococcus schleiferi Isolates of Staphylococcus schleiferi are from clinical sampling of various locations, mainly external ear canal, skin or wound. The proportion of resistance in the presented isolates of S. schleiferi (Table 5.19) seems lower than in isolates of S. pseudintermedius from dogs (Table 5.18), but also lower compared to S. aureus in horses (Table 5.16) and S. felis in cats (Table 5.23). For example the occurrence of beta-lactamase production in the tested S. schleiferi isolates was only 4%, compared to 77% in S. pseudintermedius, and 18% in both S. felis and S. aureus. However, the occurence of resistance to one substance, enrofloxacin, is relatively high for the otherwise susceptible S. schleiferi (11%) compared to S. pseudintermedius (2%), S. aureus (3%) and S. felis (0%). No further identification, to separate S. schleiferi in subspecies (subsp. schleiferi and subsp coagulans) was carried out.
60% 50% 40% 30% 20% 10% 0% 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Clindamycin
Erythromycin
Penicillin
Tetracycline
Fusidic acid
Pseudomonas aeruginosa Isolates of Pseudomonas aeruginosa are from clinical sampling of the external ear canal. Pseudomonas aeruginosa is inherently resistant to trimethoprim-sulphonamides, tetracyclines and aminopenicillins (including combinations with clavulanic acid). Svarm data
Table 5.19. Distribution of MICs and resistance (%) in Staphylococcus schleiferi isolated from various locations in dogs 2014. Antibiotic
Resistance (%) 2014 n=297
Cephalothin
aa
Distribution (%) of MICs (mg/L) ≤0.12
0.25
0.5
1
2
0
Clindamycin
4
Enrofloxacin
11
4
8
16
32
>32
100 96.3 29.0
56.2
4.0
9.8
95.3
0.3
3.7
1.0 0.3
Erythromycin
4
Fusidic acid
3
95.3
1.3
4.0
Gentamicin
0
98.7
1.3
Nitrofurantoin
0
Oxacillin
0
Penicillina
4
Tetracycline
3
Trim-Sulph.b
1
3.4
100 100
96.3
92.9
1.7
1.0
1.7
1.0
1.0
1.3
3.0
Denotes beta-lactamase production; bb Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim/sulphamethoxazole).
Table 5.20. Distribution of MICs and resistance (%) in Pseudomonas aeruginosa from dogs 2014. Clinical isolates from the external ear canal. Antibiotic
a
Resistance (%)
Distribution (%) of MICs (mg/L)
2014 n=389 a
≤0.12
0.25
0.5
1
2
Enrofloxacin
12
0.8
1.3
16.5
48.3
Colistin
1
65.6
Gentamicin
1
Colistin, 302 isolate tested.
4
8
16
20.8
6.2
6.2
28.5
5.0
0.3
0.7
88.7
8.0
2.3
0.8
32
0.3
>32
89
90
SWEDRES | SVARM 2014
Table 5.21. Distribution of MICs and resistance (%) in Pasteurella canis. Clinical isolates from dogs 2014. Antibiotic
Resistance (%) 2014 n=207
Ampicillin
0
Enrofloxacin
1
Gentamicin
a
Distribution (%) of MICs (mg/L) ≤0.12
0.25
0.5
98.6
1.0
0.5
97.6
1.9
1
<1
Tetracycline
<1
Trim-Sulph.a
0
4
8
16
32
>32
100 0.4
0
Penicillin
2
100 0.5 99.5 99.5
0.5
0.5 0.4
Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim-sulphametoxazole).
prior to 2014 cover P. aeruginosa isolates of the described category tested with polymyxin B, and all tested isolates have been sensitive to the substance. In 2014 polymyxin B was replaced by colisitin as representative for polymyxines and three of 302 tested isolates (1%) were resistant to colistin. This may be true resistance or due to methodological errors, but the isolates were not available for further analyses. A trend of gradually declining resistance to enrofloxacin, from 25% in 2009 to 14% in 2013 and 12% in 2014 could be observed. The figures for gentamicin have also dropped from 5% in 2009 to 1% in 2013-2014 (Table 5.20).
Pasteurella Isolates of Pasteurella spp. are from clinical sampling of various locations, but mainly from wound or skin, external ear canal and the respiratory tract. Pasteurella canis was the most commonly detected species of the included clincal isolates (n=207), while P. multocida was second most common (n=29). As shown in Table 5.21, resistance to antibiotics of the tested P. canis isolates are low. Furthermore, all P. multocida isolates (n=29) were susceptible to all the tested antibiotics (data not shown). Cut-off values for resistance of P. canis isolates in Table 5.21 are the same as used for P. multocida.
Cats Escherichia coli Isolates are from clinical sampling of urine, submitted either as urine or cultures from dip-slides or other agar plates. In 2014 resistance to ampicillin was still the most common trait (Table 5.22 and Figure 5.6). Since 2007, the rate of resistance has differed somewhat between the years, but overall the figures seem rather stable (Figure 5.6). Of the tested E. coli isolates in 2014, 3% (14/461) was multiresistant which is comparable to figures in 2010-2011 (3%) and 2012 (2%). Of the 14 multiresistant isolates were 12 resistant to three substances and 2 to 4 substances. All 14 of the multiresistant isolates were resistant to ampicillin, 8 to tetracycline and 7 to trimethoprim-sulphametoxazole. Five E. coli isolates were resistant to cefotaxime. Genes conferring transmissible ESBL or AmpC resistance were found in one of these isolates. For more information see ESBL-producing Enterobacteriaceae in animals.
Staphylococcus felis Isolates of Staphylococcus felis are from clinical sampling of various locations, but mainly external ear canal or other skin location, abscess or wound. S.felis is the only coagulase nega-
Table 5.22. Distribution of MICs and resistance (%) in Escherichia coli isolated from cats 2014. Clinical isolates from urine. Antibiotic
Resistance (%) 2014 n=461 b
Ampicillin
16
Cefotaxime
1
Colistin
3
Enrofloxacin
7
Gentamicin
0
Nitrofurantoin
a
Distribution (%) of MICs (mg/L) ≤0.12
93.5
0.25
3.3
0.5
1
98.9
0.2
0.9
74.6
21.9
0.7
0.2
2.0
2
4
8
16
63.8
19.7
0.9
15.6
2.5
0.6
0.3
9
Trim-Sulph. a
2
3.9 97.4
0.2
>32
2.4
0.7
0.4
99.1
0.9
81.1
5.2
<1
Tetracycline
32
25.8
71.1
1.1
8.7
2.4
Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim-sulphametoxazole); b Colisitin tested isolates n=319.
SWEDRES | SVARM 2014
tive staphylococci in this material of clinical isolates from different animal species. The proportions of resistance to the tested antibiotics in clinical isolates of S. felis (Table 5.23) seems comparable to those of S. aureus isolates from horses (Table 5.16) and lower compared to those of S. pseudintermedius in dogs (Table 5.18). For example resistance to penicillin due to beta-lactamase production was 18% in S. felis (cats) and S. aureus (horses), but 77% in S. pseudintermedius (dogs).
Figure 5.6. Resistance (%) in clinical isolates of Escherichia coli from urine of cats, 2007-2014. The number of isolates each year varies (n=131-461). 25%
Resistance
20%
15%
10%
Pasteurella Isolates of Pasteurella spp. are from clinical sampling of various locations, but mainly from wound or skin, external ear canal and the respiratory tract. Pasteurella multocida (approximately equal between subsp. septica and multocida) was the most commonly detected Pasteurella in the presented clincal material from cats (n=244), while P. dagmatis was second most common (n=20). As shown in Table 5.24 the proportion of resistance to antibiotics used in pets was low in the tested P. multocida isolates. All twenty isolates of P. dagmatis were susceptible to all the tested antibiotics (data not shown). Cutoff values for resistance of P. dagmatis isolates are the same as used for P. multocida.
5%
0%
2007
2008
2009
2010
2011
Ampicillin
Enrofloxacin
Tetracycline
Trim-Sulph.
2012
2013
2014
Nitrofurantoin
Table 5.23. Distribution of MICs and resistance (%) in Staphylococcus felis isolated from various locations in cats 2014. Antibiotic
a
Resistance (%) 2014 n=244
Distribution (%) of MICs (mg/L) ≤0.12
0.25
0.5
1
2
4
<1
Clindamycin
7
Enrofloxacin
0
Erythromycin
9
Fusidic acid
3
95.5
2.0
Gentamicin
0
99.6
0.4
Nitrofurantoin
0
Oxacillin
0
Penicillina
18
Tetracycline
1
Trim-Sulph.b
0
99.6
88.9
10.7
16
32
99.2
0.8
>32
0.4
Cephalothin
0.8
92.2
8
7.0
0.4 89.3
2.0
0.4
8.2 2.5
100
98.4 98.8
0.8
1.2
1.2
Denotes beta-lactamase production; b Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim/sulphamethoxazole).
Table 5.24. Distribution of MICs and resistance (%) in Pasteurella multocida. Clinical isolates from cats 2014. Antibiotic
Resistance (%) 2014 n=244
a
Ampicillin
0
Enrofloxacin
2
Gentamicin
2
Penicillin
0
Tetracycline
<1
Trim-Sulph.
3
a
Distribution (%) of MICs (mg/L) ≤0.12
0.25
0.5
96.3
1.6
0.4
85.2
14.3
0.4
1
2
4
8
0.4
0.4
0.4
46.3
47.5
4.1
16
32
0.8
1.2
100 0.4
98.7 94.7
2.0
0.4 0.4
Concentration of trimethoprim given, tested in concentration ratio 1/20 (trimethoprim-sulphametoxazole).
0.8 2.9
>32
91
92
SWEDRES | SVARM 2014
Indicator bacteria from animals
Escherichia coli Broilers
In programmes monitoring antibiotic resistance in the veterinary field, Escherichia coli, Enterococcus faecalis and Enterococcus faecium from the enteric flora of healthy animals or from the flora contaminating food serve as indicators for the presence of acquired resistance. The level of resistance in these so called indicator bacteria reflects the magnitude of the selective pressure from antibiotic use in an animal population. Moreover, although these bacteria are unlikely to cause disease they can be reservoirs for resistance genes that can spread to bacteria causing infections in animals or humans. Resistance in indicator bacteria contaminating meat indicates the potential exposure of humans to such reservoirs among farm animals through the food chain. In 2014, indicator bacteria from broilers and turkeys were studied. Samples of intestinal contents were collected at slaughter and cultured for E. coli and samples from broilers were also cultured for enterococci. In addition, all samples were also screened for E. coli resistant to extended spectrum cephalosporins (ESC) by selective culture on media supplemented with cefotaxime. For details on methodology see Material and methods, resistance in bacteria from animals.
Escherichia coli was isolated from 197 (99%) of 200 samples cultured. The majority of isolates (75%) was susceptible to all antibiotics tested, but one fourth of the isolates was resistant to one antibiotic or more (Table 6.1). Resistance to sulphonamides (13%), quinolones (nalidixic acid and ciprofloxacin) (11%), tetracycline (10%), ampicillin (9%) and trimethoprim (8%) were the most common traits. Sixteen isolates (8%) were multiresistant and all of these had resistance to sulphonamides and ampicillin in their phenotype. Twelve of these isolates were resistant also to trimethoprim and tetracycline. Since the start of the monitoring in year 2000, resistance to single antibiotics has been below 15% and mostly stable. This favorable situation is likely due to the limited use of antibiotics in broiler production in Sweden (see Use of antibiotics in animals). Resistance to sulphonamides, tetra cycline, ampicillin, trimethoprim and to quinolones has, however, gradually increased in recent years, although the levels this year are lower than in 2012 except for sulphonamides (Fig 6.1). The reasons for the increase are not known
Table 6.1. Resistance (%) and multiresistance (%) in indicator Escherichia coli from broilers and turkeys, 2014. Data on indicator Escherichia coli from previous Svarm-reports are given for comparison. Resistance (%) Antibiotic
ECOFF
Broilers
Turkeys
Broiler meat
Calves
Laying hens
Pigs
Pig meat
Sheep
Horses
Dogs
2014 n=197
2014 n=59
2012 n=92
2013 n=197
2012 n=61
2011 n=167
2011 n=20
2006-09 n=115
2010-11 n=274
2012 n=74
9
25
18
1
3
13
30
2
2
9 1
(mg/L)
Ampicillin
>8
Cefotaxime
>0.25
0
2
0
0
2
<1
0
0
0
Ceftazidime
>0.5
0
2
-
0
-
-
-
-
-
-
Chloramphenicol
>16
0
3
0
0
0
4
0
0
<1
0
>0.06
11
3
4
1
5
2
10
<1
<1
3
>2
0
0
1
0
0
0
0
-
<1
0 0
Ciprofloxacin Colistin
>2
0
0
3
0
2
1
0
3
<1
Meropenem
Gentamicin
>0,12
0
0
-
-
-
-
-
-
-
-
Nalidixic acid
>16
11
2
4
<1
5
2
0
0
<1
0
Sulphamethoxazole
>64
13
17
16
2
8
17
10
7
15
4
Tetracycline
>8
10
24
14
3
13
8
0
<1
2
8
Tigecycline
>1
0
0
-
-
-
-
-
-
-
-
Trimethoprim
>2
8
5
7
1
5
11
10
2
16
1
84
Multiresistancea
a
Susceptible to all above
75
44
66
95
80
72
70
89
83
Resistant to 1
14
43
18
3
7
13
10
9
2
8
Resistant to 2
3
4
7
2
7
4
5
2
12
7
Resistant to 3
2
10
3
<1
7
5
15
<1
Resistant to >3
6
5
Ciprofloxacin and nalidixic acid as well as cefotaxime and ceftazidime considered as one antibiotic class.
6
2 <1
<1
SWEDRES | SVARM 2014
Figure 6.1. Percent resistance in Escherichia coli from broilers 2000-2014. The number of isolates each year varies (n=194-307). 15%
10%
10%
Resistance
Resistance
15%
5%
5%
0%
0% 2000
2002
2004
2006
2008
2010
2012
Ampicillin
Sulphamethoxazole
Streptomycin
Tetracycline
2000
2014
2002
2004
2006
Ciprofloxacin
2008
2010
Nalidixic acid
2012
2014
Enrofloxacin
Table 6.2. Distribution of MICs and resistance (%) in Escherichia coli from intestinal content from broilers (n=197) and turkeys (n=59), 2014. Antibiotic
Source
Resistance %
Broilers Turkeys Broilers Azithromycin Turkeys Broilers Cefotaxime Turkeys Broilers Ceftazidime Turkeys Broilers Chloramphenicol Turkeys Broilers Ciprofloxacin Turkeys Broilers Colistin Turkeys Broilers Gentamicin Turkeys Broilers Meropenem Turkeys Broilers Nalidixic acid Turkeys Broilers Sulphamethoxazole Turkeys Broilers Tetracycline Turkeys Broilers Tigecycline Turkeys Broilers Trimethoprim Turkeys Ampicillin
9 25 NRa NRa 0 2 0 2 0 3 11 3 0 0 0 0 0 0 11 2 13 17 10 24 0 0 8 5
Distribution (%) of MICs (mg/L) ≤0.016
Not relevant because no ECCOFF is available
0.06
0.12
0.25
0.5
1
2
4
8
16
32
64
4.6 56.9 28.4 1.0 3.4 44.1 27.1 3.6 54.8 40.1 1.5 6.8 37.3 55.9 100 98.3
4.6 8.5
7.1 3.4
3.6
512 1024 >1024
9.1 25.4
1.7 100 96.6
84.3 88.1
128 256
1.7 100 98.3
1.7
1.7
1.5 1.7
0.5
0.5 99.5 0.5 100 76.1 21.3 2.5 66.1 30.5 3.4
99.5 98.3
0.5 1.7 88.3 0.5 96.6 1.7 13.2 5.1 89.8 0.5 74.6 1.7
≤0.016 a
0.03
0.03
0.06
0.12
99.5 100 53.8 67.8
35.0 27.1
3.6
0.25
0.5
1
9.1 44.7 23.7 0.5 1.7
25.4 42.4 0.5 5.1
4.1 11.9 5.1 5.1 3.6 8.5 8.5
12.7 11.9
0.5 7.6 5.1 2
4
8
16
32
64
128 256
512 1024 >1024
93
SWEDRES | SVARM 2014
but could be due to spread of multiresistant clones without a selective pressure from antibiotic use. Using selective culture, ESC resistant E. coli was isolated from 72 (36%) of the 200 samples of intestinal content from broilers. One isolate had resistance genes of the CTX-M-1 group and 70 isolates genes of the CIT-group. In one isolate genes conferring transmissible ESBL or AmpC resistance were not detected. For details and comments see Notifiable diseases.
Turkeys Escherichia coli was isolated from 59 of 60 samples cultured (98%). About half of the isolates (44%) was susceptible to all antibiotics tested but 33 isolates (56%) were resistant to at least one substance (Table 6.1). Resistance to ampicillin (25%), tetracycline (24%) and sulphonamides (17%) were the most common traits. Six isolates (10%) were multiresistant and of these, four isolates were resistant to both ampicillin and tetracycline in addition to other antibiotics. One isolate was resistant to cefotaxime and ceftazidime but genes conferring transmissible ESBL or AmpC resistance were not detected. Resistance to single antibiotics is of the same magnitude as in 2013 when E. coli from turkeys were first studied in Svarm. The total number of isolates tested 2013-2014 is, however, small and the results should therefore be interpreted with caution. Resistance in E. coli from turkeys is about as prevalent as among isolates from broilers and involves the same antibiotics (Table 6.1). Quinolone resistance, however, seems to be more common in E. coli from broilers than in isolates from turkeys and the opposite applies for ampicillin, tetracycline and sulphonamide resistance. Using selective culture, ESC resistant E. coli was isolated from 12 (20%) of the 60 samples cultured. Genes conferring transmissible ESBL or AmpC resistance were not found in any of these isolates. For details and comments see Notifiable diseases.
Enterococcus Broilers A total of 27 isolates of Enterococcus faecalis and 187 isolates of Enterococcus faecium were obtained from 200 samples cultured. In E. faecalis the majority of isolates (70%) was resistant to at least one antibiotic but no isolate was multiresistant (Table 6.3). Resistance to narasin (41%) or tetracycline (37%) were the most common traits and resistance to erythromycin or bacitracin occurred at lower levels. The number of isolates tested is small and conclusions on occurrence of resistance must be made with caution. The findings are however in agreement with previous data from Svarm and the levels of resistance seem stable or slightly decreasing (Fig 6.2). In E. faecium the majority of isolates (85%) was resistant to at least one antibiotic and six isolates (3%) were multiresistant (Table 6.4). Resistance to narasin was the most common trait (77%) and resistance to erythromycin, bacitracin, tetracycline, ampicillin, gentamicin, virginiamycin and vancomycin also occurred but at much lower levels. One isolate was phenotypically resistant to vancomycin (MIC 8 mg/L) but vanA or vanB genes were not detected in the isolate when tested by PCR. The findings are in agreement with previous data from Svarm and the levels of resistance seem stable or slightly decreasing (Fig 6.2). Use of antibiotics in poultry is uncommon in Sweden (see Use of antibiotics in animals) and it is unlikely that the observed resistance to erythromycin, tetracycline and bacitracin is due to a direct selection pressure from use of antibiotics on poultry farms in Sweden. The high occurrence of resistance to the ionophore narasin in both E. faecalis and E. faecium are, however most likely a consequence of the common use of narasin as coccidiostat in broiler production (see Use of antibiotics in animals). Notably resistance to narasin in enterococci from other animals, where narasin is not used, is rarely found in Sweden (Table 6.3 and 6.4).
Figure 6.2. Percent resistance in Enterococcus faecalis and Enterococcus faecium from broilers, 2000-2014. The number of isolates each year varies; E. faecalis n=35-57 and E. faecium n=136-204 Enterococcus faecium
Enterococcus faecalis 100%
80%
80% Resistance
100%
Resistance
94
60%
40%
40% 20%
20%
0%
0% 2000
60%
2002
2004 Bacitracin Narasin
2006
2008
2010 Erythromycin Tetracycline
2012
2014
2000
2002
2004 Bacitracin Narasin
2006
2008
2010 Erythromycin Tetracycline
2012
2014
SWEDRES | SVARM 2014
Table 6.3. Resistance (%) and multiresistance (%) in Enterococcus faecalis from broilers, 2014. Data on indicator Enterococcus faecalis from previous Svarm-reports are given for comparison. Resistance (%) Antibiotic
ECOFF
Broilers
Calves
Broiler meat
Laying hens
Pigs
Pig meat
Horses
Sheep
Dogs
2014 n=27
2013 n=11
2012 n=78
2012 n=20
2011 n=22
2011 n=29
2010-11 n=34
2006-09 n=24
2006 n=135
(mg/L)
Ampicillin
Bacitracina Chloramphenicol Erythromycin
>4
0
0
0
0
0
0
0
0
<1
>32a
7
0
23
10
0
0
0
0
1
>32
0
0
5
0
0
0
18
0
7
>4
7
0
13
10
43
0
21
0
14
Gentamicin
>32
4
0
1
0
4
0
21
0
<1
Kanamycin
>1024
0
0
0
0
4
0
21
0
4
Linezolid
>4
0
0
1
0
0
0
0
0
0
Narasin
>2
41
0
37
0
0
0
0
0
1
>512
0
0
5
0
17
3
9
4
9
Tetracycline
>4
37
0
36
45
74
7
44
8
32
Vancomycin
>4
0
0
0
0
0
0
0
0
0
Virginiamycin
>32
0
0
0
0
0
0
0
0
0
Susceptible to all above
30
100
27
45
17
90
56
92
25
Resistant to 1
44
37
45
35
10
24
4
38
Resistant to 2
26
29
10
43
4
27
Streptomycin
Multiresistance (%)
a
Resistant to 3
1
Resistant to >3
5
2 4
21
7
MIC in U/ml
Table 6.4. Resistance (%) and multiresistance (%) in Enterococcus faecium from broilers, 2014. Data on indicator Enterococcus faecium from previous Svarm-reports are given for comparison. Resistance (%) Antibiotic
ECOFF
Broilers
Calves
Broiler meat
Laying hens
Pigs
Pig meat
Horses
Sheep
Dogs
2014 n=187
2013 n=42
2012 n=10
2012 n=36
2011 n=22
2011 n=1
2010-11 n=27
2006-09 n=15
2006 n=29
(mg/L)
Ampicillin
>4
2
0
0
0
0
0
15
0
0
Bacitracin
>32a
10
5
40
3
9
0
0
0
3
>32
0
0
0
0
0
0
0
0
0
>4
8
10
0
6
9
0
0
0
28
Gentamicin
>32
0
2
0
0
0
0
0
0
0
Kanamycin
>1024
0
2
0
0
9
0
0
0
0
>4
0
0
0
0
0
0
0
0
0 7
Chloramphenicol Erythromycin
Linezolid Narasin
>2
77
0
80
0
0
0
0
0
>128
0
0
0
0
13
0
7
7
0
Tetracycline
>4
4
2
30
11
13
0
4
7
17
Vancomycin
>4
<1
0
0
0
0
0
0
0
0
Virginiamycin
>4
<1
0
10
8
4
100
4
0
0
Susceptible to all above
15
15
83
78
74
74
87
62
Resistant to 1
71
63
12
17
13
22
13
30
Resistant to 2
11
21
5
6
4
Resistant to 3
2
1
Resistant to >3
1
Streptomycin
Multiresistance (%)
a
MIC in U/ml
9
100
4
6
2
95
96
SWEDRES | SVARM 2014
Table 6.5. Distribution of MICs and resistance (%) in Enterococcus faecalis (n=27) and Enterococcus faecium (n=187) from broilers, 2014. Antibiotic
Bacterial species
Resistance %
Ampicillin Bacitracin
a
Chloramphenicol Erythromycin Gentamicin Kanamycin Linezolid Narasin Streptomycin Tetracycline Vancomycin Virginiamycin
E. faecalis E. faecium E. faecalis E. faecium E. faecalis E. faecium E. faecalis E. faecium E. faecalis E. faecium E. faecalis E. faecium E. faecalis E. faecium E. faecalis E. faecium E. faecalis E. faecium E. faecalis E. faecium E. faecalis E. faecium E. faecalis E. faecium
0 2 7 10 0 0 7 8 4 0 0 0 0 0 41 77 0 0 37 4 0 <1 0 <1
Distribution (%) of MICs (mg/L) ≤0.12
MIC in U/ml
0.5
1
2
4
8
46.0
44.4 13.4
51.9 20.9 3.7 42.2
3.7 15.5
2.7
1.6 48.1 23.0 29.6 7.5
33.3 51.9
33.3 29.9
4.3
5.9 70.4 16.6 75.9 14.8 11.1 6.4 3.7 3.7 13.9 56.7
3.7 85.2 26.7
16
32
64
128
256
40.7 12.3
2.1
3.7
3.7 5.3
3.7 1.1
0.5
1.1
63.0 19.8
37.0 34.8
52.4 18.5 1.1
74.1 26.7 14.8 1.6
25.9 1.1 3.7
32
64
128
0.5 7.4 2.7 3.7
7.4 1.6
18.5 2.1
29.6 13.9 3.7 3.2
25.9 81.3
≤0.12 a
0.25
0.25
48.1 51.3 3.7 1.6
22.2 34.8 25.9 14.4
512
1024 2048 >2048
7.4 2.1 3.7
36.9
4.3
0.5
256
512
40.7 66.3 10.7 2.1
17.6
2.1
1.1
0.5
0.5 66.7 0.5
14.8
8
16
22.2 1.1
34.2
33.3 12.3 77.8 98.4 3.7 26.2
3.7
36.9
14.8 2.1
0.5
1
2
4
1024 2048 >2048
SWEDRES | SVARM 2014
97
The results of the project are currently being prepared for publication but some preliminary data are presented here. In all four countries resistance to ampicillin, streptomycin, sulphonamides or trimethoprim was less common in E. coli from organic than from conventional pigs but there were also differences in resistance between countries within production type. In some countries also resistance to tetracycline, chloramphenicol, ciprofloxacin, nalidixic acid or gentamicin was less common in organic pigs. In three of the countries the median sample proportion of tetracycline resistant intestinal E. coli was lower in organic than in conventional pigs, except in Sweden where the resistance to tetracycline was generally low (Figure). Differences in the proportion of tetracycline-resistant E. coli between countries within production type were also observed with lower median proportions in Sweden and Denmark compared to France and Italy. The results show that in each of the four countries resistance in intestinal E. coli is less common in organic than in conventional pigs and additionally that there are differences in resistance between countries within production type. This illustrates that country specific and production specific factors may interact, both contributing to occurrence of resistance. Thus, the findings suggest that not only a low consumption of antibiotics but also other factors may contribute to occurrence of resistance. If those factors could be identified, the information would be useful for designing measures to mitigate resistance and therefore future studies should be focused on identifying them.
Valuable information on risk factors for antibiotic resistance could be gained by exploring and comparing resistance among farm animals raised in different production systems. In organic pig production the use of antibiotics is more restricted than in conventional production, but there are also other differences. Factors such as herd size, animal contacts, feeding regimes, outdoor access and space allowance per pig could hypothetically also influence the occurrence of resistant bacteria. Several different aspects of antibiotic resistance in organic and conventional pig production were studied in the recently completed research project SafeOrganic funded by the CORE Organic II Funding Bodies, for further information see: www.coreorganic2.org. One of the studies in the project focused on differences in antibiotic resistance between organic and conventional pig production. Briefly, colon content and/or faeces from healthy pigs in Denmark, France, Italy and Sweden was collected. The goal was to include 25 herds of each production type from each country and two pigs from each herd. Samples were collected at abattoirs or on farms from pigs close to slaughter. Samples were cultured for Escherichia coli that were subsequently tested for antibiotic susceptibility by determining the minimum inhibitory concentration (MIC) of ten antibiotics using microdilution. MICs were interpreted by ECOFFs issued by EUCAST (www.eucast.org). In addition, as a quantitative measure of resistance in individual pigs the proportion of tetracycline resistant E. coli in colon contents or faeces was determined from the ratio of counts of colonies on culture plates with tetracycline and without tetracycline.
Proportion tetracycline-resistant E. coli
FIGURE. The distribution of the proportion of tetracycline resistant Escherichia coli in samples of colon contents or faeces from 430 pigs in 110 conventional (Conv.) and 93 organic (Org.) herds in four European countries (median, 25% and 75% percentiles (box), maximum and minimum (whiskers)). n= number of samples; p= the significance level for the difference between distributions in conventional and organic herds for each country and sample type (Kruskal-Wallis test for non-normal distributions) 2
1,5
1 0,60
0,5
0,51 0,29
0
0,06 0,03 n=52 n=52 Conv. Org. Denmark (p=0,0029)
n=49 Org.
France (p=0,0046) Colon
Max (whiskers)
n=30 Conv.
n=33 Org.
Sweden (p=0,2374)
75% percentile (box)
0,14
0,00
0,00 n=50 Conv.
Median
n=50 Conv.
n=50 Org.
Italy (p<0,0001)
25% percentile (box)
0,00 n=29 Conv.
Faeces
0,00 n=35 Org.
Sweden (p=0,2198)
Min (whiskers)
Partners of SafeOrganic: Technical University of Denmark, National Food Institute, Denmark (coordinator); Istituto Zooprofilattico Sperimentale delle Venezie, Italy; Agency for Food, Environment, and Occupational Health Safety, France; National Veterinary Institute, Sweden; University of Copenhagen, Denmark; Veterinary Research Institute, Czech Republic
In focus
SafeOrganic – studies on antibiotic resistance in organic and conventional pig production in EU
98
SWEDRES | SVARM 2014
SWEDRES | SVARM 2014
Background data, material, metods and references Demographics and denominator data Human beings Table 7.1. Population by county and age group. December 31st 2014. 0-6 years
7-19 years
20-64 years
65-79 years
80 years-
All ages
202 618
314 385
1 309 052
251 770
85 217
2 163 042
Stockholm Uppsala
28 966
49 684
205 011
46 544
15 276
345 481
Södermanland
22 363
41 534
153 272
44 984
15 416
277 569
Östergötland
35 599
63 294
251 874
63 345
23 736
437 848
Jönköping
28 352
51 707
191 540
49 641
19 995
341 235
Kronoberg
15 243
27 467
105 382
27 771
11 293
187 156
Kalmar
16 761
32 009
129 149
40 896
15 059
233 874
Gotland
4 017
7 710
32 129
9 937
3 368
57 161
Blekinge
11 457
21 535
84 353
25 957
9 455
152 757
Skåne
110 088
180 090
739 599
178 187
66 105
1 274 069
Halland
25 314
46 487
170 867
47 124
17 048
306 840
135 824
229 918
943 911
222 346
83 085
1 615 084
Västra Götaland Värmland
19 821
37 496
153 705
45 227
17 566
273 815
Örebro
23 426
41 291
161 296
43 803
15 579
285 395
Västmanland
20 507
37 425
145 942
40 530
14 650
259 054
Dalarna
20 662
39 148
153 213
47 050
17 276
277 349
Gävleborg
20 389
39 106
154 663
47 159
16 653
277 970
Västernorrland
17 974
34 286
133 889
41 151
14 856
242 156
9 590
17 603
70 767
20 718
7 783
126 461 261 112
Jämtland Västerbotten
20 510
36 499
151 526
38 544
14 033
Norrbotten
17 337
34 236
141 789
41 806
14 268
249 436
806 818
1 382 910
5 582 929
1 374 490
497 717
9 644 864
Sweden
Table 7.2. Population in Sweden 2000-2014 - Number represent the population by December 31st 2014. 2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
Population 8882792 8909128 8940788 8975670 9011392 9047752 9113257 9182927 9256347 9340682 9415570 9482855 9555893 9644864
Table 7.3. Number of admissions and patient-days in somatic medical care in Sweden, 2009-2013 Year
Admissions
2010
1473835
Patient-days 6958834
2011
1496324
6979857
2012
1514608
6859956
2013
1385962
6144504
Table 7.4. Number of admisions and paitent-days in somatic medical care 2013. Data represent production by acute care hospitals in the counties. County
Admissions
Patient-days
Blekinge
23906
119436
Dalarna
46829
197578
Gotland Gävleborg
9776
41628
37348
161958 186426
Halland
42884
Jämtland
18719
87576
Jönköping
56083
240222
Kalmar
42855
160023
Kronoberg
26423
124862
Norrbotten
38793
184320
Skåne
193500
868293
Stockholm
235036
897561
Södermanland
36294
180197
Uppsala
56542
287668
Värmland
40654
191352
Västerbotten
50639
241877
Västernorrland
37843
171817
Västmanland
38094
176128
241812
1131076
Örebro
45003
216246
Östergötland
66929
278260
1488460
6776274
Västra Götaland
Sweden
99
SWEDRES | SVARM 2014
Table 7.5. Denominator data from the microbiological laboratories 2014.
43496
9280
1336
122
876
10490
Clostridium difficile (toxinpositive)
663
Escherichia coli
4645
Streptococcus pyogenes
Blood (pair of bottles)
Faeces Clostridium difficile (toxin)
19054
Faeces SSYC
10626
Urine
Throat 4212
Number of positive cultures 2014
Streptococcus pneumoniae
10520
Number of positive samples 2014
Staphylococcus aureus
0
Screen MRB
965
General culture
Aleris Medilab
Nasopharynx
Laboratory
Cerebrospinal fluid (CFS)
Number of analyses 2014
Blood (pair of bottles)
100
272
Borås
19605
189
4923
1859
6820
3267
23994
5085
1902
2521
4797
364
479
7220
145
Eskilstuna (Unilabs)
13611
148
5857
2900
7441
2469
28971
4790
1875
2303
4607
768
692
7654
271
Falun
19028
213
4443
1358
11377
4896
31001
3932
2019
1856
5491
542
567
9075
279
Gävle
13736
248
2712
969
12615
25249
24328
3119
2282
1978
5072
427
360
8629
386
Göteborg
43979
1525
1952
3447
19581
39446
66251
10561
4540
5550
11144
583
1136
16126
468
Halmstad
13570
136
2597
2211
8239
8542
26596
6038
2056
2030
4670
520
586
8600
323
Jönköping
22300
236
6100
2960
17100
23300
39500
7050
2920
3070
8020
500
501
11790
460
Kalmar
13301
146
4009
1667
8502
4444
28756
4446
1651
1811
4950
553
434
9605
267
Karlskrona/ Växjö
19500
193
6339
2054
11210
8376
35000
6067
3642
2363
4632
571
586
10300
482
Karlstad Karolinska Stockholm
19139*
262
3638
2358
13422
8054
36751
4096
2024
3735*
6260
459
627
9931
244
88553
2801
30932
9075
79760 264327
158701
21354
11502
11606
30717
2646
3026
42474
1323
Linköping
24696
959
7194
2771
23505
9707
46676
5462
3487
2644
4776
427
699
9060
333
Lund/Malmö
71033
1912
17841
11222
30969
49947
161792
25717
10253
9390
22842
2204
2751
44779
1223
Skövde (Unilabs)
14064
137
3967
2629
14721
11009
55829
9325
2968
1415
7751
282
703
13715
333
S:t Göran (Unilabs)
12115
88
7121
2200
12243
52109
46630
8955
3419
1278
6196
658
865
11876
494
Sunderby Luleå
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Sundsvall
14194
152
2129
1291
6704
5749
27328
3655
2107
2121
3824
406
389
8562
327
NÄL Trollhättan
20320
234
1936
1450
9089
17518
32439
3837
1906
2394
4999
258
469
9020
255
Umeå
16079
531
3673
1795
8217
7478
30847
3326
1843
1599
4990
508
630
9769
385
Uppsala
21196
957
7187
2616
16662
15143
35915
5148
3581
2366
6519
662
599
9410
562
4669
36
2109
382
3013
NP
6764
935
488
460
1560
208
144
2171
36
Västerås
Visby
14164
165
2713
1646
9883
4135
28771
4293
2230
2149
4171
320
347
9436
367
Örebro
17530
251
10437
1677
15380
8695
33882
5795
2936
2019
7049
1137
693
8727
380
7612
110
2512
1158
6879
4734
18379
2539
1294
953
3216
333
NP
5994
242
65907 363958 597648 1068597 164805
74261
67733 172898
15999
18159 294413
9857
Östersund Total
524959
11629 152841
*not pair; NP, not performed; NA, data not available
Animals Agricultural statistics are provided by Statistics Sweden in collaboration with the Board of Agriculture. The statistics are published annually as a Yearbook of Agricultural Statistics and continuously as Statistical Messages (SM) available on the websites for Statistics Sweden (www.scb.se) or the Board of Agriculture (www.jordbruksverket.se). Annual figures on number of animals and holdings are given in Table 7.6 & 7.7 and on numbers and volumes of animals slaughtered in Table 7.8. & 7.9. In brief, the number of dairy cows, pigs and laying hens has decreased notably over the last three decades while
during the same time, herd size has increased. In the same period, the number of beef cows, sheep and chickens reared for slaughter has increased. Data on the number of dogs and cats are also available from the Board of Agriculture. In a study 2012 the numbers of dogs and cats in Sweden were estimated to 784 000 and 1 159 000, respectively. The number of households with dogs was estimated to 572 000 and the number of households with cats to 745 000. This represents an increase by 8% in the number of dogs and a decrease by 8% in the number of cats since the most recent study carried out in 2006.
SWEDRES | SVARM 2014
Table 7.6. Number of livestock and horses (in thousands) 1980-2014. From Yearbook of agricultural statistics for selected years, Statistical message JO 24 SM 1101 and the statistical database of the Board of Agriculture. Animal Species
1980a
1985a
1990
1995
2000
2005
2010
2012
2013
2014
656
646
576
482
428
393
348
348
346
344
Cattle Dairy cows Beef cows Other cattle >1 year Calves <1 year
71
59
75
157
167
177
197
193
193
186
614
570
544
596
589
527
513
479
499
490
595
563
524
542
500
509
479
481
468
472
1 935
1 837
1 718
1 777
1 684
1 605
1 537
1 500
1 506
1 492
Ewes and rams
161
173
162
195
198
222
273
297
286
287
Lambs
231
252
244
266
234
249
292
314
297
301
392
425
406
462
432
471
565
611
585
588
290
260
230
245
206
188
156
142
150
145
1 254
1 127
1 025
1 300
1 146
1 085
937
851
851
857
1 170
1 113
1 009
769
566
539
427
370
397
376
2 714
2 500
2 264
2 313
1 918
1 811
1 520
1 363
1 397
1 378
Hens
5 937
6 548
6 392
6 100
5 670
5 065
6 061
6 735
6 874
6 549
Chickens reared for laying
2 636
2 159
2 176
1 812
1 654
1 697
1 647
1 551
1 708
1 713
8 573
8 708
8 568
7 912
7 324
6 762
7 707
8 286
8 582
8 262
122
130
283d
363
Total, cattle Sheep
Total, sheep Pigs Boars and sows
Fattening pigs >20 kg Piglets <20kg
b
c
Total, pigs Laying hens
Total, hens Turkeys Total, turkeys
80
Horses Total, horses
a For 1980 and 1985 only cattle and sheep at premises with more than 2 ha counted; b Before 1995, the figure denotes pigs above 3 months of age; c Before 1995, the figure denotes pigs below 3 months of age; d Data from 2004.
Table 7.7. Number of holdings with animals of different types, 1980-2014. From the Yearbook of agricultural statistics for selected years and the statistical database of the Board of Agriculture. Animal Species
1980
1985
1990
1995
2000
2005
2010
2012
2013
2014
Dairy cows
44 143
35 063
25 921
17 743
12 676
8 548
5 619
4 968
4 668
4 394
Beef cows
12 436
10 310
10 883
17 069
13 861
12 821
12 190
11 375
11 092
10 663
Other cattle >1 year
63 179
52 652
42 696
39 160
30 457
24 808
20 295
18 182
17 824
17 094
Calves <1 year
62 314
52 001
41 986
36 542
27 733
22 888
18 494
17 001
16 306
15 706
Cattle
Total holdings with cattle
70 503
58 872
47 292
41 990
32 063
26 179
21 586
19 561
18 962
18 210
Sheep
10 238
10 595
9 749
10 037
8 089
7 653
8 657
9 263
8 869
8 912
Pigs
26 122
19 937
14 301
10 753
4 809
2 794
1 695
1 318
1 281
1 282
Laying hens
23 603
17 531
12 900
9 593
5 678
4 916
3 703
3 876
4 149
3 878
5 093
2 714
1 875
1 405
715
634
487
673
629
760
Broilers
234
181
217
242
260
Turkeys
383
102
56 000a
78 000
Chickens reared for laying
Horses a
Data from 2004.
126
101
102
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Table 7.8. Number of animals slaughtered (in thousands) at slaughterhouses, 1980-2014. From the Yearbook of agricultural statistics for selected years and and the statistical database of the Board of Agriculture. Animal Species
1980
1985
1990
1995
2000
2005
2010
2011
2012
2013
2014
574
584
523
502
490
433
425
429
392
391
405
Cattle Cattle >1 year Calves < 1 year Total, cattle Sheep Pigs Broilers
130
152
70
30
39
33
27
27
29
27
26
704
736
593
532
529
466
453
456
421
418
431
302
328
280
189
202
206
255
262
260
281
258
4 153
4 283
3 653
3 743
3 251
3 160
2 936
2 845
2 592
2 556
2 553
40 466a
36 410a
38 577a
61 313
68 617
73 458
78 507
78 182
76 840
83 265
89 681
495
574
466
452
420
Turkeys a
Data supplied by the National Food Administration.
Table 7.9. Quantity of livestock slaughtered (in 1000 tonnes) at slaughterhouses, 1990-2014. From the Yearbook of Agricultural Statistics for selected years and and the statistical database of the Board of Agriculture. Animal Species
1990
1995
2000
2005
2010
2012
2013
2014
139.5
140.1
145.4
131.4
133.5
121.0
121.9
127.5
6.8
3.2
4.4
4.5
4.3
4.5
4.2
4.1
146.3
143.3
149.8
135.9
137.8
125.5
126.1
131.5
5.0
3.5
3.9
4.1
5.0
5.0
3.9
4.1
Pigs
293.1
308.8
277.0
275.1
263.5
233.7
234.6
235.3
Broilers
44.0a
73.6a
89.9
96.2
112.0
109.7
116.8
128.7
3.2
3.0
2.9
3.3
Cattle Cattle >1 year Calves < 1 year Total, cattle Sheep
Turkeys a
Data supplied by the National Food Administration.
SWEDRES | SVARM 2014
Materials and methods, consumption of antibiotics Legal framework and distribution of medicines Marketing of drugs in Sweden is regulated by the Medicinal products Act, which applies both to human and veterinary medicinal products. According to this Act, a medicinal product may not be sold until it has been granted marketing authorisation by the Medical Products Agency (MPA). In case there are no authorised medicinal products for a certain condition, the MPA can permit special licence prescription for a medical product for a specified pharmacy, prescriber or clinic. Medicinal products have to be dispensed through pharmacies, which are supplied by drug wholesalers or manufacturers. In outpatient care, antibiotic drugs (including medicated feed in veterinary use) may only be sold on prescriptions, ApoDos or requisitions. Prescribers (veterinarians or doctors) are not permitted to own a pharmacy or to otherwise sell medicinal products for profit. Veterinarians may deliver products to the animal care-taker in relation to examination of a case for self cost (no profit). In hospital care, both for human and animal, antibiotic drugs are bought on requisitions. All pharmacies in Sweden are required to provide statistics on sales of all products on a daily basis to the Swedish eHealth Agency. This agency maintains a national database with sales statistics for all drugs and provides statistics to the competent national and regional authorities and to others on a commercial basis. Feed mills may only mix antimicrobials in feed if they are controlled and authorised by the Swedish Board of Agriculture (SBA). The feed mills normally acquire the antibiotic products from a pharmacy. All quantities of antibiotic products used by feed mills are reported yearly to the SBA as part of the feed control. Mixing of antibiotics in feed may also take place on farms; provided that the SBA has inspected and authorised the establishment for the purpose. In such cases, the premix is sold by a pharmacy following prescriptions from a veterinarian.
The ATC classification system and defined daily doses (DDD) Since 1988, the Anatomical Therapeutic Chemical (ATC) and ATCvet classification system recommended by the WHO is used in Sweden for national drug statistics. For drugs sold for use in humans, to facilitate drug utilisation studies from a medical point of view, the concept of defined daily dose (DDD) is used as a unit of comparison in drug statistics. The DDD for a drug is established on the basis of the assumed average dose per day for the drug given to adults for its main indication. If possible, the DDD is given as the amount of active substance. The DDDs are usually equal for all dosage forms of a preparation. The statistical data systems of the Swedish eHealth Agency are upgraded yearly according to the recommendations made by the WHO Collaborating Centre for Drug Statistics methodology in Oslo, Norway. The DDDs used in this report are shown in Table 7.10. The
sales of drugs are presented as number of DDDs per 1 000 inhabitants and day (DDD/1 000 and day), which give an estimate of the proportion of the population daily exposed to a particular drug. This figure is a rough estimate and should be interpreted with caution.
Antimicrobial consumption in humans Swedish national statistics on drug utilization Since 1975, the National Corporation of Swedish Pharmacies regularly produces sales statistics on drugs, for the country as a whole and for individual counties. The sales are registered as number of DDDs, cash value and number of packages. Out-patient care data includes information on the sales of drugs dispensed on prescription by all Swedish pharmacies by the prescription survey, running since 1974. The statistical material was until 1995 built of samples of dispensed prescriptions. From 1996 all prescriptions dispensed by pharmacies are included. From 1999, ApoDos (individually packed doses of drugs often dispensed to elderly) is also included in the survey. Recorded data are trade name, quantity, patient fee, total cost, sex and year of birth of the patient. Data can be expressed as DDD/1000 and day or number of prescriptions/1000 inhabitants. Hospital care data includes drugs delivered by all hospital pharmacies to the hospital departments (se bellow chapter Completeness of data). The sales are expressed as cash value, number of packages and number of defined daily doses. Following the re-regulation of the pharmacy market in Sweden in July 2009, the responsibility for collection of medicines statistics was transferred to the core infrastructure supplier for all pharmacies, Apotekens Service. In January 2014, the activity in the state-owned company Apotekens Service were transferred to the Swedish eHealth Agency. The Swedish eHealth Agency (eHälsomyndigheten) aims to contribute to improved health care, care and the nation’s health by pursuing development of a national e-health infrastructure. They are responsible for Sweden’s national drug statistics.
Completeness of data Concerns have been raised that after the reregulation, the statistics on sales of medical products to hospitals in Sweden is less complete than before. In Sweden, pharmacies are required by law to report sales statistics to the Swedish eHealth Authority. However, after the reregulation of the pharmacy market, counties can choose to manage drug supplies to hospital by them self. If so, the counties are not required to report data to the national database. Since October 2013, one county has chosen to organize their own drug supplies organization for hospitals. Therefore, no national database with complete sales statistic is available at this time. Efforts have been made to complement the data from the Swedish eHealth Agency with data from counties.
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Definitions of DDD 2014 Table 7.10. DDD for all antibiotic substances (J01) sold in Sweden in 2014. Substances are sorted according to ATC-code.
DDD (g)
J01AA02 – doxycycline
0.1
J01EA01 - trimethoprim
J01AA04 – lymecycline
0.6
J01EC02 - sulfadiazin
J01AA06 - oxitetracycline
1
J01EE01 - sulfamethoxazol and trimethoprim
J01AA07 - tetracycline
1
J01FA01 - erythromycin
J01AA12 - tigecycline
0.1
J01FA01- erythromycin erythylsuccinat tablets
DDD (g) 0.4 0.6 1.92 1 2
J01BA01 - chloramphenicol
3
J01FA06 - roxithromycin
0.3
J01CA01 - ampicillin
2
J01FA09 - clarithromycin - oral
0.5
J01CA04 - amoxicillin
1
J01FA10 - azithromycin - parenteral
0.5 0.3
J01CA08 - pivmecillinam
0.6
J01FA10 - azithromycin - oral
J01CE01 - benzylpenicillin
3.6
J01FA15 - telithromycin
0.8 1.8
J01CE02 - fenoximethylpenicillin
2
J01FF01 - clindamycin - parenteral
J01CF02 - cloxacillin
2
J01FF01 - clindamycin - oral
J01CF05 - flucloxacillin
2
J01GB01 - tobramycin - parenteral
1
J01GB01 - tobramycin - oral inhalation solution
0.3
14
J01GB01 - tobramycin - oral inhalation powder
0.112
J01CR02 - amoxicillin and enzyme inhibitor-oral J01CR05 - piperacillin and enzyme inhibitor
1.2 0.24
J01DB01 - cefalexin
2
J01GB03 - gentamicin
J01DB03 - cefalotin
4
J01GB06 - amikacin
J01DB05 - cefadroxil
2
J01GB07 - netilmicin
0.35
3
J01DC02 - cefuroxime- parenteral J01DC02 - cefuroxime - oral J01DC08 - loracarbef J01DD01 - cefotaxime J01DD02 - ceftazidime J01DD04 - ceftriaxon J01DD08 - cefixime J01DD14 - ceftibuten
0.24 1
J01MA01 - ofloxacin
0.4
0.5
J01MA02 - ciprofloxacin - parenteral
0.5
0.6
J01MA02 - ciprofloxacin - oral
1
4
J01MA06 - norfloxacin
0.8
4
J01MA12 - levofloxacin
0.5
2
J01MA14 - moxifloxacin
0.4
0.4
J01XA01 - vancomycin
0.4
J01XA02 - teicoplanin
2 0.4
2
J01XB01 - colistin
J01DF01 - aztreonam - parenteral
4
J01XC01 - fusidic acid
1.5
J01DF01 - aztreonam - inhalation
0.225
J01DE01 - cefepime
3 MU
J01XD01 - metronidazole
1.5
J01DH02 - meropenem
2
J01XE01 - nitrofurantoin
0.2
J01DH03 - ertapenem
1
J01XX04 - spectinomycin
J01DH51 - imipenem and enzyme inhibitor
2
Data sources and inclusion criteria Data on sales of antibiotics in outpatient care is obtained from the Swedish eHealth Agency. For the overall statistics, the data include all antimicrobial products marketed in Sweden in the ATC classes J01 and J02. The data includes all sales of these products, even if the antimicrobial (J01 and J02) is prescribed by a veterinarian. Measures used are defined daily doses per 1000 inhabitants and day (DDD/1000 and day) and prescriptions per 1000 inhabitants. Every purchase of a medicine prescribed in outpatient care is also recorded in the Prescribed Drug Register, held by the Swedish National Board of Health and Welfare. This register provides the
3
opportunity to link each prescription to an individual, which makes it possible to investigate the actual number of individuals or the fraction of the population treated with a specific medicine. Antibiotic consumption in hospital care is measured as DDD/1000 inhabitants and day and DDD/100 patient-days or admissions. The number of DDDs is obtained from the Swedish eHealth Agency and from local medicines statistics systems in the counties. The National Board of Health and Welfare has provided data on patient-days and admissions to hospitals. Admission is calculated as number of discharges (one patient can be discharged and admitted multiple times if
SWEDRES | SVARM 2014
transferred between wards during one hospital stay). Patientday is calculated as each additional day during one hospital stay. The number of patient-days and admissions includes data on somatic medical care by each county (to be distinguished from consumption of the county’s inhabitants).
The Swedish Prescribed Drug Register Since July 2005, the Swedish National Board of Health and Welfare supplies an individually based register on all drugs prescribed and dispensed in outpatient care. Among others this data gives information on the number of individuals treated with at least one course of antibiotics during a specific period of time, i.e. number of users per 1000 inhabitants and year (Users/1000/year). It is also possible to follow the number of purchases per person.
Number of admissions and patient-days Each of the 21 county councils in Sweden deliver once a year data to the National Patient Register kept by The National Board on Health and Welfare. Administrative data within hospital care include, among others, date of admission, date of discharge and length of stay. Data for 2014 is not available until August 2015, denominator data from 2013 are used in some figures in this report. The number of admissions and patient-days in Swedish somatic medical care (produced by acute care hospitals) 2009-2013 is shown in Table 7.3. The National Board of Health and Welfare keeps a searchable database at the web, http://www.socialstyrelsen.se/statistik.
Antibiotic consumption in animals Data sources, inclusion criteria and analysis Raw data on sales is obtained from the Swedish eHealth Agency and represent the sales of products containing antibiotics sold by pharmacies. When products are dispensed for animals, the animal species as given on the prescription is recorded and reported to the Swedish eHealth Agency jointly with the sales, unless the product is sold for use in veterinary practice (on requisition). For the overall statistics, the data include all products with antibiotics as active substance marketed in Sweden and sold for use in terrestrial animals in the ATCvet classes QA07, QG04, QJ01 and QJ51. Medicinal products authorised for human use but prescribed for use in animals is not included in the overall statistics. However, to follow prescriptions for dogs, information on number of packages sold per product-presentation belonging to QA07, QJ01 and drugs authorised for use in humans and prescribed for dogs belonging to J01 were retrieved. That data-set closely corresponds to out-patient use. Data are retrieved as number of packages sold per product presentation and per animal species, if recorded. Calculation to kg active substance is done based on product information obtained from the national product register of the MPA. The term consumption is used for sales from pharmacies to private and professional animal care-takes as well as to veterinary clinics.
In rare cases, premixes mixed in medicated feed may be delivered from feed mills without the sales being recorded by a pharmacy. Examination of the reports by all feed mills to the SBA shows that this happened only once during 2005-2009 (a total quantity of 40 kg active substance). The ionophoric antibiotics are presently regulated as feed additives and not sold through pharmacies. However, the SBA collects figures on sales of ionophores from the feed mills as a part of the feed control system. As the source differs, data on ionophores are given only in the table on sales of products for mixing in feed or water in Table 3.9.
Completeness of data Before July 2009, all Swedish pharmacies belonged to a state owned co-operation. Since, the market has been reregulated and today there are many pharmacies competing on the market. All pharmacies are obliged to report their sales to the Swedish eHealth Authority. Concerns have been raised that after the reregulation, the statistics on consumption of veterinary medicinal products with a general marketing authorisation in Sweden is less complete than before 2010. SVA attempted to produce an estimate of the lack of completeness for the consumption of antibiotics in 2013 (see Swedres-Svarm 2013, Use of antimicrobials for animals). In brief, it was assumed that the lack of completeness primarily affects products that are typically sold from pharmacies to veterinarians on requisition. This is most common for products for parenteral administration. The ten injectable products with highest sales from pharmacies during 2013, in kg active substance, were selected. Information on sales to pharmacies for all marketed productpackage types of these products was collected from Marketing authorisation holders. Number of packages sold and amount of active substance sold from wholesalers to pharmacies were compared to the sales from pharmacies to veterinarians and animal owners. The sales from wholesalers to pharmacies expressed as kg active substance were 11% higher than the sales from pharmacies. A similar study was performed for the consumption of antibiotics in 2014. One of the products included for 2013 was not available on the market for most of the year, and was therefore excluded. The difference between sales to and from pharmacies of the remaining nine products, expressed as kg active substance was 8 and 14% for 2013 and 2014, respectively. The difference varied between classes (9 – 16% in 2014). The above estimate was limited to products for injection with general marketing authorisation in Sweden. Other types of products are less likely to be affected by the observed lack of completeness. Based on this assumption, the overall difference in total sales as kg active substance to and from pharmacies in 2014 was calculated to 8%. The figure is uncertain as the difference varied between classes of antibiotics, and there may be some lack of completeness for certain other products.
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Products sold with special licence Previously, most antimicrobial products sold with special licence (products prescribed and sold on exemption from general Swedish market authorization) were also included. However, in 2011 it was noticed that the information on sales of products with special licence was less complete than in previous years. The information in the database of the Swedish eHealth Agency on sales of such products still seems incomplete. Efforts have been made to identify companies who might have statistics on sales of products sold with special licence to the Swedish market. Products formulated for
administration via feed or water were prioritized, as were those with fluoroquinolones and other products where the number of granted licences was above 30. No effort was made to get additional data on sales of products for intramammary use, as the amounts sold have historically been very low. Whenever the information on number of packages sold per product-packtype from the Swedish eHealth Agency was lower than that obtained from pharmaceutical companies, the figure was adjusted. This means that for some products, the figures may represent a slight overestimate of sales from pharmacies as they may include products kept in stock.
SWEDRES | SVARM 2014
Materials and methods, resistance in bacteria from humans Antibiotic Susceptibility testing The microbroth dilution method is the internationally accepted reference method for susceptibility testing to which other methods are compared. Clinical microbiology laboratories in Sweden have a long tradition of using disk diffusion antibiotic susceptibility testing (AST). This method is quantitative (diameter of inhibition zones measured in mm) but results are normally interpreted to give a qualitative “recommendation”: S (susceptible, sensitive), I (intermediate) and R (resistant). The disk diffusion method has been successfully standardized by the Swedish clinical microbiology laboratories in collaboration with the former SRGA-M, which since 2011 is replaced by NordicAST, a Nordic AST Committee with representatives from Denmark, Norway and Sweden. Until 2009 all laboratories used the methodology based on ISA medium and a semi-confluent bacterial inoculum as recommended by SRGA-M. From 2011 all laboratories have adopted the new European method as described by EUCAST, based on Mueller Hinton agar and an almost confluent inoculum (equivalent to a 0.5 McFarland turbidity standard). The disk diffusion method is still the most commonly used routine method for susceptibility testing. It can also be used as a screening method which in some cases needs to be followed up by methods for gene detection (e.g. MRSA, VRE) and in other instances by MIC-determination (e.g. beta-lactam resistance in pneumococci, chromosomally mediated betalactam resistance in Haemophilus influenzae), and still in others by methods for enzyme detection (e.g. beta-lactamase detection in Haemophilus influenzae and Neisseria gonorrhoeae). Internal and external quality assurance and quality control of susceptibility testing is performed by each laboratory. Internal quality control includes using international QC strains regularly (preferably on a daily basis) and analysing data in relation to national guidelines. Validation of susceptibility testing can also be done by histogram analysis of consecutive clinical isolates (see www.eucast.org). External quality control is often done by participation in UK-NEQAS and/or other international programmes, whereas quality assurance is one of the features of the Swedish ”100-strains”, also referred to as ResNet or RSQC programme.
National surveillance of antibiotic resistance Surveillance regulated in the Communicable Disease Act Statutory notifications of certain communicable diseases are regulated in the Communicable Disease Act (SFS 2004:168, SFS 2004:255). With the exception of certain sexually transmitted infection (STI), and from 2007 ESBL-producing Enterobacteriaceae, both the clinician caring for a patient with a notifiable disease (clinical notification) and the laboratory diagnosing the pathogen causing the disease (laboratory notification) are obliged to notify. This double notification significantly enhances the sensitivity of the surveillance system.
Notification shall be done within 24 hours, in duplicate to the County Medical Officer for Communicable Disease Control (smittskyddsläkare) and to the Swedish Public Health Agency. Notifications, with the exception of STI, are done with full person identification. The clinical notification shall also include information on the likely source and route of infection, as well as other information of epidemiological importance. Infections (or colonisation) with different antibiotic resis tant pathogens are included in the list of notifiable diseases. Streptococcus pneumoniae with bensylpenicillin MIC > 0.5 mg/L (PNSP) have been notifiable since 1996 (MIC > 1 mg/L from 2012). Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis and Enterococcus faecium (VRE) have been notifiable since 2000. Since 1st February 2007 ESBL-producing Entero bacteriaceae were made notifiable by laboratory notifications. The definition of an ESBL was extended in 2009 to include not only ESBLs inhibited by clavulanic acid (now referred to as ESBLA) but also plasmid-mediated AmpC enzymes (ESBLM) and carbapenemase enzymes (ESBLCARBA). All notifications are entered into the national computerized surveillance system, SmiNet2. At the Public Health Agency of Sweden, the clinical and laboratory notification for each case are merged and checked for errors. If data are missing, contact persons in the counties are asked to supplement the information. As an important complement to the notifications, the MRSA, VRE and PNSP isolates are sent for epidemiological typing. For MRSA spa-typing is the primary typing method, for VRE it is pulsed-field gel electrophoresis (PFGE), and for PNSP serotyping. Depending on needs also other molecular biology methods are used, e.g. MLST. Tuberculosis (TB) is a notifiable disease, irrespective of drug resistance. On a voluntary basis the TB laboratories are reporting all drug-resistant isolates of Mycobacterium tuberculosis and M. bovis to the Public Health Agency of Sweden. All resistant isolates are sent to the Public Health Agency of Sweden for epidemiological typing, using restriction fragment length polymorphism (RFLP). The feedback of notification data is done monthly on the webpage (http://www.folkhalsomyndigheten.se) and yearly in this and other reports. Data on drug-resistant TB is also annually published in “the Swedish Tuberculosis Index”. Possible epidemiological links between patients from different counties, as identified from the epidemiological typing results and the notifications, are communicated to the persons in charge of the communicable disease control actions at the county level. Gonorrhoea and invasive infections caused by Neisseria meningitidis are also notifiable. The descriptions of materials and methods for these pathogens are found under their respective result section.
107
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Swedish combined surveillance and QC programme (RSQC surveys) further developed into ResNet since 2002 In 1994 a model for the concomitant surveillance of antimicrobial resistance and quality assurance of antimicrobial susceptibility testing was devised. In Sweden there are at present 26 clinical microbiology laboratories, each covering a county (or part of county) of Sweden. The demographics of the laboratories, their geographic areas and their corresponding populations are well characterized. The antimicrobial susceptibility testing methods of the laboratories have been standardized through the combined work of the former SRGA-M (since 2011 replaced by NordicAST) and the microbiology laboratories. Each year the laboratories are asked to collect quantitative data (zone diameters) for defined antibiotics in 100-200 consecutive clinical isolates of a defined set of bacterial species. Since 1994, Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae have been part of this yearly program. Since 2001 Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa have been part of these surveys. The number of antibiotics tested for each pathogen has varied between 4 and 6. From 2002 web-based software (ResNet) will receive the aggregated data from the laboratories and, following approval of registered data by one of two web administrators, instantly displayed it in the form of resistance frequencies on the geographical areas on a map of Sweden. Behind each resistance frequency the distribution of zone diameters or MICs together with the relevant demographic data are directly accessible. The software will accept both MIC and zone distributions of well-characterized data sets. The graphs presenting the data are designed to include all necessary information in order for the graphs to be used on their own (in presentations etc). A recently introduced feature enables each laboratory to view all its own data and also to link this information to a website of its own local health care system.
EARS-Net The European network of national surveillance systems of antimicrobial resistance (EARSS) performed on-going surveillance of invasive infections of Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, and Enterococcus faecalis/ faecium, and monitors variations in antimicrobial resistance over time and place. From 2005 invasive isolates of Klebsiella pneumoniae and Pseudomonas aeruginosa are also part of the scheme. In 2014 Acinetobacter species was added to the programme. During 2009 a transition of the EARSS management from RIVM in the Netherlands to ECDC in Stockholm was prepared, and from 1st January 2010 the network, renamed as EARS-Net, is coordinated from ECDC.
Data collected by EARS-Net should be routinely generated quantitative data (MICs or inhibition zones), but the data presented is in the format of susceptibility categories (SIR). External quality assurance exercises have so far been carried out by EARS-Net in cooperation with UK-NEQAS once every year. Results of those exercises have shown that participating laboratories were capable of delivering good quality susceptibility data, indicating that the overall resistance rates as monitored through EARS-Net are accurate. The participation from laboratories in Sweden is coordinated through the Public Health Agency of Sweden, where electronic data collection, validation and verification of specific resistance mechanisms are performed. Sweden, because of its well organised network of clinical laboratories and high quality of routine susceptibility testing, is one of the largest contributors of national data to EARS-Net.
Surveillance of invasive isolates additional to EARS-Net data Data on invasive isolates on all positive blood cultures were obtained from seven laboratories in 2014 that are using the same laboratory information system (ADBakt). Their total catchment population is at present 4.7 million, thus representing 48% of the Swedish population. From these laboratories data for the pathogens specified by the EARS-net network are retrieved, but also data on all other bacterial pathogens consecutively isolated from blood cultures. In the SWEDRES reports from 2007 data for Streptococcus pyogenes, Streptococcus agalactiae and Haemophilus influenzae are presented.
Sentinel surveillance A national surveillance programme for Clostridium difficile was initiated by SMI in 2009. The programme included both a voluntary laboratory reporting system of all new cases of C. difficile infection (CDI) through SmiNet2 and a determination of resistance and epidemiological typing of isolates from the clinical microbiology laboratories. All C. difficile strains isolated during weeks number 11 and 39 were sent to SMI for typing by PCR ribotyping and antibiotic susceptibility testing. Susceptibility testing of gastrointestinal pathogens such as Salmonella, Shigella, Campylobacter spp. and Helicobacter pylori is not performed on a regular basis by clinical laboratories. Existing data are mainly derived from special investigations by devoted researchers / laboratories
SWEDRES | SVARM 2014
Materials and methods, resistance in bacteria from animals Sampling strategy Antibiotic resistance as notifiable diseases ESBL
ESBLA and ESBLM-producing Escherichia coli were isolated from the same samples as the indicator bacteria, i.e. from caecal content from broilers and turkeys, see below. Clinical isolates from cats, dogs, and horses were submitted to the Dept. of Animal Health and Antimicrobial Strategies, SVA as bacterial strains. MRSA and MRSP
Findings of MRSA and MRSP in animals are notifiable in Sweden and hitherto the majority of isolates from notified incidents has been confirmed using molecular methods at SVA. Monitoring of MRSA in dairy cattle was performed by screening isolates of beta-lactamase producing Staphylococcus aureus from routine submissions of milk samples sent to SVA. From each submission where beta-lactamase producing S. aureus was found, one isolate, selected by convenience, was tested. Monitoring of MRSA in pigs was performed by sampling in all Swedish nucleus and multiplying herds (n=39). Weaned pigs 5-12 weeks old were sampled, 6 pigs per box, 15 boxes per herd. The 6 sampled pigs in one box were sampled by scrubbing the skin behind one ear with the same sterile compress.
Zoonotic pathogens Salmonella
Salmonellosis in animals is a notifiable disease in Sweden and isolates from each notified incident are confirmed at SVA. Data presented in Svarm are from susceptibility testing of these isolates. The summary for each year includes one isolate of each serovar from each warm-blooded animal species in notified incidents. An exception is isolates from cats and wild birds from which a subset of isolates are selected by convenience. In addition, isolates from incidents previously notified and still under restrictions are included in the yearly statistics. Also included are isolates obtained in the salmonella surveillance programme from samples collected at slaughter (carcass swabs, neck skins and lymph nodes). Campylobacter
Campylobacter spp. were isolated from caecal content from healthy broilers sampled at slaughter within the Swedish Campylobacter programme in which whole caeca are collected from each batch of broilers slaughtered. In 2014, 363 flocks were positive for Campylobacter. From these, 102 isolates of Campylobacter jejuni, each representing one flock was randomly selected for susceptibility testing. The isolates were stored in -70°C until tested.
Clinical isolates from animals Clinical isolates included are from routine bacteriological examinations of clinical submissions or post-mortem examinations. Part of the isolates of Actinobacillus pleuropneumoniae from pigs, part of the isolates of Pasteurella spp. from calves and all isolates of S. aureus from dairy cows are, however, isolated from samples collected in surveys initiated within the Svarmpat programme. In pigs, isolates of E. coli are from the gastro-intestinal tract and isolates of Brachyspira spp. from faecal samples. Isolates of Pasteurella spp. from pigs are isolated from nasal swabs collected within a control programme for atrophic rhinitis in nucleus and multiplying herds or from tissue samples from lungs taken post mortem. Isolates of A. pleuropneumoniae in pigs emanate from tissue samples from lungs sampled post mortem. In cattle, isolates of E. coli are from samples from the gastrointestinal tract or from milk samples. Isolates of Pasteurella spp. are from the respiratory tract. In sheep, isolates of M. haemolytica and Bibersteinia treahalosi are from tissue samples from lungs taken post mortem. In horses, isolates of E. coli are from the genital tract of mares, Streptococcus zooepidemicus from the respiratory tract and S. aureus from skin samples. In dogs, isolates of E. coli are from urine samples, Staphyl ococcus pseudintermedius from skin samples, Staphylococcus schleiferi from various organs (mainly external ear canal, skin or wound), and Pseudomonas aeruginosa from the external ear. In cats, isolates of E. coli are from urine samples and Staphylococcus felis from various organs (mainly external ear canal or other skin locations, abscess or wound). In farmed fish, isolates of Aeromonas salmonicida subsp. achromogenes, Flavobacterium columnare and Flavobacterium psychrophilum are from post mortem examinations.
Indicator bacteria Broilers
Indicator bacteria, i.e. E. coli and Enterococcus faecalis and Eenterococcus faecium, were isolated from caecal content of healthy broilers sampled at slaughter. Samples cultured were from the Swedish Campylobacter programme – see above. From these samples, 100 were selected by convenience in March-April and 100 in September-October. Each sample is from a unique flock but not always from a unique production site. Samples cultured were collected at six abattoirs that in 2014 accounted for approximately 98% of the total volume of broilers slaughtered. The number of samples from each abattoir was roughly proportional to the annual slaughter volume of the abattoir. Turkeys
Indicator E. coli was isolated from caecal content of healthy turkeys sampled at slaughter. Sampling was performed at two abattoirs in Sweden, from January to December. Each sample is from a unique flock but not always from a unique production site.
109
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SWEDRES | SVARM 2014
Isolation and identification of bacteria Antibiotic resistance as notifiable diseases ESBL
ESBLA and ESBLM-producing E. coli were isolated by culture on MacConkey agar with cefotaxime (1 mg/L) after incubation overnight at 37°C, both without and with prior enrichment in MacConkey broth with cefotaxime (1 mg/L). Briefly, approximately 0.5 g of caecum content from broilers was diluted in 4.5 mL saline. After thorough mixing, 0.1 mL of this suspension was spread on MacConkey agar with cefotaxime (1 mg/L) and incubated overnight at 37°C. Furthermore, 1 g of caecum content was diluted in 9 ml MacConkey broth with cefotaxime (1 mg/L) and incubated at 37°C overnight. From the MacConkey broth 100 µL was spread on MacConkey agar with cefotaxime (1 mg/L) and incubated overnight at 37°C. One lactose positive colony with morphology typical for E. coli growing on MacConkey agar with cefotaxime were sub-cultured on horse-blood agar (5% v/v) and further tested for ESBL detection. MRSA
In the screening for MRSA among isolates of beta-lactamase producing S. aureus from dairy cows, isolates were susceptibility tested using microdilution (see below). Isolates with MICs of oxacillin >1 mg/L and/or cefoxitin >4 mg/L were tested for presence of mecA and mecC with PCR (see below). In the screening of pigs, each compress was incubated in 25 mL Mueller-Hinton broth with 6.5% NaCl overnight at 37°C. Then 1 mL was transferred to Tryptic Soy broth with 3.5 mg/L cefoxitin and 75 mg/L aztreonam and incubated overnight at 37°C. Thereafter 10 µL were streaked on selective agar plates (Brilliance, Oxoid) and on oxblood plates and incubated at 37°C for 24 and 48 h. Suspected MRSA colonies were tested by PCR for presence of mecA and mecC genes.
Zoonotic pathogens Salmonella
Salmonella was isolated and identified at the Dept. of Bac te ri ology, SVA or at regional laboratories in accordance with standard procedures. All samples within official control programmes are cultured according to the procedures detailed by the MSRV (ISO-EN 6579:2002/ Amd 1:2007). Confirmatory identification and serotyping was performed according to the procedures of Kaufmann and White. Isolates of Salmonella Enteritidis were phage-typed by The Public Health Agency of Sweden, Solna using the Colindale scheme. As from 2013 other serovars are not phagetyped. Campylobacter
Campylobacter spp. from broilers were isolated and identified at the Dept. of Bacteriology, SVA. Samples were cultured according to ISO/DIS 10272-1:2014 for detection of thermophilic Campylobacter spp. by direct cultivation on mCCDA and incubation at 42°C. Identification was based on colony morphology, microscopic appearance including motility and
the following phenotypic characteristics: production of oxidase, catalase and hippurate hydrolysis reaction. With these tests, hippurate-positive C. jejuni were identified.
Clinical isolates from animals Most clinical isolates were isolated and identified with accredited methodology, following standard procedures at SVA. Part of the isolates of Pasteurella spp. from pigs and cattle, isolates of M. haemolytica and B. trehalosi from sheep and part of the isolates of E. coli from cattle were isolated and identified following standard procedures at a regional laboratory.
Indicator bacteria Escherichia coli
Approximately 0.5 g of caecum content from broilers was diluted in 4.5 mL saline. After thorough mixing, 0.1 mL of this suspension was spread on MacConkey agar and incubated overnight at 37°C. One lactose positive colony with morphology typical for E. coli was sub-cultured onto horse-blood agar (5% v/v), after which the isolate was tested for production of tryptophanase (indole). Only lactose and indole positive isolates with typical morphology were selected for susceptibility tests. Enterococci
Caecum content from broilers was diluted as described for E. coli and 0.1 mL was spread on Slanetz-Bartley (SlaBa) agar and incubated at 37°C for 48 h. Four colonies, randomly chosen, were sub-cultured on bile-esculin agar and blood agar (37°C, 24 h). Colonies with morphology consistent with enterococci, and with a positive reaction on bile-esculin agar were identified to species level by MALDI-TOF MS. Mass spectra were compared against the MALDI Biotyper database using the MALDI Biotyper 3.0 Realtime Classification (RTC) software (Bruker Daltonik GmbH, Bremen, Germany). If available, one isolate of E. faecium and one isolate of E. faecalis from each sample were tested for antibiotic susceptibility.
Susceptibility testing Microdilution At SVA, bacteria from animals are tested for antibiotic susceptibility with accredited methodology using dilution methods in cation adjusted Mueller-Hinton broth (CAMHB) (Difco). Tests are performed following the standards for microdilution of the Clinical and Laboratory Standards Institute (CLSI, 2013a). The microdilution panels used, VetMIC, are produced at Section of Substrate Production, SVA and Sensititre are produced at Trek diagnostics LTD. Different panels are used depending on the bacterial species tested and the purpose of the investigation (monitoring or clinical diagnostics). Minimum inhibitory concentration (MIC) is recorded as the lowest concentration of an antibiotic that inhibits bacterial growth. Some adaptations from the CLSI standard are employed. For Pasteurella spp. three different protocols are used at SVA.
SWEDRES | SVARM 2014
Either by dilution in CAMHB supplemented with 5-10% horse serum followed by incubation in aerobic atmosphere, 37°C for 16-18 hours, or by dilution in Haemophilus test medium (HTM) followed by incubation in CO2, 37°C for 16-18 hours. Also dilution in CAMHB supplemented with 5-10% horse serum and incubation in CO2, 37°C for 16-18 hours was used. For testing of A. pleuropneumoniae dilution in HTM broth is used followed by incubation in CO2 at 37°C for 16-18 hours. Also, S. zooepidemicus is tested using CAMHB supplemented with 5-10% horse serum followed by incubation at 37°C for 16-18 hours. Susceptibility of Campylobacter spp. is tested according to the CLSI standard M45-A2 for fastidious bacteria (CLSI, 2010). Susceptibility of Brachyspira hyodysenteriae and B. pilosicoli, is tested by a broth dilution method described by Karlsson et al. (2003). The antibiotics are dried in serial twofold dilutions in tissue culture trays with 48 wells per plate. The wells were filled with 0.5 mL of a suspension of bacteria in brain heart infusion broth (BHI) with 10% foetal calf serum (1x106-5x106 CFU/ml). The trays were incubated in an anaerobic atmosphere at 37°C for four days on a shaker. Bacteria from fish are tested for antibiotic susceptibility by broth microdilution adapted for aquatic bacteria according to CLSI (2014a). Phenotypic confirmatory tests for production of extended spectrum beta-lactamases (ESBLs) in E. coli was performed with and without clavulanic acid in Sensititre EUVSEC2 microdilution panels and interpreted according to CLSI (CLSI, 2013b).
Genotyping Suspected isolates of MRSA were confirmed by detection of the nuc, mecA and mecC genes applying real-time PCR as described by Pichon et al. (2012). Spa-typing, a single locus sequence typing method using the polymorphic region X of the protein A gene, was performed on all isolates confirmed as MRSA, according to Harmsen et al. (2003) and the specific spa-type was determined using BioNumerics® (Applied Maths). MRSP spa-typing was performed according to Moodley et al. (2009) and MLST according to the MLST Scheme at http://pubmlst.org/spseudintermedius/. PCR was performed for identification of ESBLM (PerezPerez and Hanson 2002), ESBLA (Woodford et al. 2006), genes coding OXA-1 group, TEM-groups and SHV-groups (Fang et al. 2006) and ESBLCARBA (Poirel et al. 2011). The specific gene variants were determined by sequencing using in-house primers and Big-Dye™ v1.1./3.1. or submitted to Macrogene Inc. (South Korea) for sequencing.
Quality assurance system Laboratories performing antibiotic susceptibility testing at SVA are accredited according to SS-EN ISO/IEC 17025 by the Swedish Board for Accreditation and Conformity Assessment (SWEDAC) to perform antibiotic susceptibility tests with microdilution methods. In addition, Dept. of
Bacteriology is accredited for isolation and identification of animal pathogens and of Salmonella and Campylobacter according to the same standard. For susceptibility tests of zoonotic, pathogen and indicator bacteria, Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Staphylococcus aureus CCUG 15915 (analogue to ATCC 29213) and Campylobacter jejuni CCUG 11284 (analogue to Campylobacter jejuni ATCC 33560) were included as quality controls. Relevant control strains were also included and evaluated at least once weekly for animal pathogens. For testing of Brachyspira, the B. hyodysenteriae type strain B78T ATCC 27164T was used for quality control. Dept. of Animal Health and Antimicrobial Strategies participates in two proficiency tests for antibiotic susceptibility testing. These are arranged by the European Union Reference Laboratory - Antimicrobial Resistance and as national ring trial. Likewise, Dept. of Bacteriology participates in proficiency tests concerning isolation and identification of Salmonella spp. and general clinical veterinary bacteriology and susceptibility tests.
Data handling Records on Salmonella and animal pathogens such as source of cultured sample, identification results, antimicrobial susceptibility etc. were registered in a databases at SVA. Data for indicator bacteria was recorded in an Access database.
Cut-off values for resistance For interpretation of MICs from susceptibility testing of zoonotic bacteria (Salmonella and Campylobacter) and indicator bacteria (Escherichia coli and enterococci) epidemiological cut-off values (ECOFF) issued by EUCAST (www.eucast. org) are used. When no ECOFF is issued, a value based on MIC distributions obtained in the Svarm program is used. This approach was used also for interpretation of narasin MICs for E. faecium because ECOFF (>4 mg/L) cuts through MIC distributions for E. faecium from some animal categories studied in Svarm (e.g. broilers) in a manner not in agreement with the concept of wild-type distributions. ECOFFs are used when available also for clinical isolates from animals. When ECOFFs are not available, or the range of concentrations tested precludes use of a recommended value, values based on MIC distributions obtained in the Svarm programme are used but clinical breakpoints issued by CLSI (CLSI, 2013b) are also taken into consideration. ECOFFs classify isolates with acquired reduced susceptibility as non-wild type. In Svarm, non-wild type isolates are called resistant. This classification is relevant for monitoring purposes, but it should be understood that resistance defined in this manner not always implies clinical resistance.
111
SWEDRES | SVARM 2014
>1
>8
>0.5 >4
Ceftazidime
>0.5
Ceftiofur
>1
>1
>2
Cephalothin
Ciprofloxacin
>2
>32
>0.06
>0.5
>32
>0.5
>16
>16
>0.06
Colistin Doxycycline
>2
>2
>0.12
>0.12
Erythromycin
>2
>16
>16
>0.06
>0.06
>1
>4 >4
>8
>4
>0.25
>0.25
>2
>0.25
>4
>4
>16
>8
>1
>2
Kanamycin Linezolid >16
>16
>32
>32
>1024
>1024
>4
>4
>16
Narasin
>2
>2
>4
>0.25
>0.5
>0.5
>1
>1
>16
>4
>4
>0.5
>4
>2
>16
>4
>16 >2
>8
>8
>2
>8
>16
>16
Neomycin
>8 >32
>8
>16
>8
>4 >32
Oxacillin
>0.5
>1
c
c
>1
>16
>16
>0.25
Oxolinic acid >0.5
>0.5
Polymyxin B
>4
Spiramycin Streptomycin
>2
>4
>512
>128
Sulphametoxazole Tetracycline
>1
>1
>1
>2
>4
>4
>16
>8
>256 >8
>0.12
>8
>2
>4
>2
MIC in U/mL; b Concentration of trimethoprim given, tested with sulphamethoxazole in concentration ratio 1/20; c beta-lactamase production.
Tylosin Tylvalosin Valnemulin
>16
>8
>8
>1
>8
>1
Trim & sulphab
a
>16
>0.25
Tigecycline a
>16 >64
Tiamulin
Trimethoprim
>8
>2
Nitrofurantoin
Penicillin
>4 >4
Fusidic acid
Nalidixic acid
>1
>0.5
Enrofloxacin
Gentamicin
>2 >2
Clindamycin
Florfenicol
Streptococcus zooepidemicus >8
Cefoxitin
Chloramphenicol
Staphylococcus aureus
Staphylococcus pseudintermdius, S. felis, S. scheliferi
>0.5
Salmonella enterica
>0.25
Cefotaxime
Pseudomonas aeruginosa
>8
Pasteurella multocida
>8
>32
Klebsiella pneumoniae
Escherichia coli (pathogen)
>4
>4 >32
Flavobacterium psycrophilum
Escherichia coli (indicator)
>8
Enterococcus faecium
>8
Bacitracina
Enterococcus faecalis
Campylobacter coli
>1
Campylobacter jejuni
Ampicillin
Brachyspira hyodysenteriae
Antbiotic
Aeromonas salmonicida
Table 7.11. Cut-off values (mg/L) for resistance. Values in red are current (March 2015) EUCAST epidemiological cut-off values (ECOFFs), blue underlined values deviate from ECOFFs, red underlined values are CLSI ECOFFs and for values in black, ECOFFs are not defined.
Actinobacillus pleuropneumonia
112
>1
>0.25
>1
>4
>16 >1 >0.12
Vancomycin
>4
>4
Virginiamycin
>32
>4
MIC in U/mL; b Concentration of trimethoprim given, tested with sulphametoxazole in concentration ratio 1/20; c beta-lactamase production.
>2 >0.5
>2 >2
>0.5
>4
SWEDRES | SVARM 2014
SVARM 2000-2014 The number of isolates of different matrices reported in Svarm since 2000 is presented below.
Table 7.12. Salmonella enterica, number of isolates 2000-2014. Source Warm-blooded animals
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
67
52
49
101
68
105
101
112
122
117
82
71
71
86
77
2010
2011
2012
2013
2014
Cold-blooded animals
17
Table 7.13. Campylobacter spp., number of isolates 2000-2014. Source
2000
2001
Cattle
67
Pigs
98
Broilers
50
2002
2003
2004
2005
2006
2007
2008
2009
68 105 100
100
109
46
97
100
83
38
100
100
Broiler meat
102 111
Meat (different sources)
74
Water
19
Table 7.14. Indicator Escherichia coli, number of isolates 2000-2014. Source
2000
Cattle
293
Pigs
260
2001
2002
2003
2004
2005
2006
2007
2008
342
349
167
19
20
314 308
303
390
274
296
306
300
2010
2011
2012
223
Pig meat Broilers
2009
296
2013
2014
197
181
194
77
92
Broiler meat Laying hens
197
61
Turkeys Horses
55
59
2013
2014
274
Dogs
257
Willow grouse
74
19
Wild boars
87
Sheep
115
Table 7.15. Indicator Enterococcus faecalis and E. faecium, number of isolates 2000-2014 (E. faecalis/E. faecium). Source
2000
2001
Cattle
22/71
Pigs
56/48 52/106
2002
2003
2004
2005
2006
2007
13/98 87/71
24/151 49/204 57/189
48/163
2009
2010
22/22
17/3
29
28/197
35/136
44/136
81/17
78/10
Laying hens
20/36
Horses
34/27
Dogs
Sheep
2012
11/42
68/39
Broiler meat
Wild boars
2011
10/24
55/47
Pig meat Broilers
2008
135/29 12/35 24/15
27/187
113
114
SWEDRES | SVARM 2014
Table 7.16. Clinical isolates from animals, number of isolates 2000-2014. Animal species & bacterial species
2000
2001
2002
2003
2004
2005
2006
87
39
24
2007
2008
2009
2010
2011
2012
2013
2014
40
15
15
58
30
29
Cattle Escherichia coli (enteric)
220
Escherichia coli (uterine)
60
Escherichia coli (udder)
169
Klebsiella spp. (udder) Pasteurella spp.
142
44 254
Staphylococcus aureus (udder)
24
100 100
27
100
Streptococcus dysgalactiae (udder)
100
Streptococcus uberis (udder)
100
96
32
14
27
80
37
41
39
39
39
87
Fusobacterium necrophorum
95
74
41
Pigs Actinobacillus pleuropneumoniae
18
Brachyspira hyodysenteriae
50
84 75
109
Brachyspira pilosicoli Escherichia coli (enteric)
399
Pasteurella spp.
82
340
39
24
39
57
33
36
37
100
31
26
23
15
24
9
7
7
8
7
93
57
72
44
31
24
13
16
17
12
13
325
298
93
83
102
94
91
74
142
118
38
25
24
10
17
24
95
19
340
386
75
Staphylococcus hyicus
20
Streptococcus equisimilis
82
Poultry (laying hens) Escherichia coli (infection)
70
Sheep Staphylococcus aureus (udder)
25
Fusobacterium necrophorum
24
Mannheimia haemolytica and Bibersteinia trehalosi
44
Fish Aeromonas salmonicida subsp. achrom.
67
20
23
8
14
5
10
9
Flavobacterium columnare
30
16
10
5
8
3
5
9
Flavobacterium psychrophilum
42
27
24
21
27
31
23
61
210
236
174
196
140
229
Horses Actinobacillus spp. Escherichia coli (genital) Rhodococcus equi Streptococcus zooepidemicus
40 323
103
73
20
301
174
166
188
188
163
150
185
161
124
273
174
175
174
180
159
187
Staphylococcus aureus
152
43
311
140
123
129
308
131
135
145
139
132
599
803
666
407
840
943
Dogs Escherichia coli (urinary)
185
183
204
234
247
304
366
425
503
Pasteurella canis
207
Pasteurella multocida
231
Pseudomonas aeruginosa Staphylococcus pseudintermedius
234 145
156
133
102
159
126
89
220
258
261
313
353
178
309
389
381
444
388
229
566
513
Staphylococcus schleiferi
297
Cats Escherichia coli (urinary) Beta-hemolytic streptococci
46
52
55
74
95
131
170
245
236
274
310
404
461
184
Pasteurella multocida
244
Staphylococcus felis
244
SWEDRES | SVARM 2014
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115
116
SWEDRES | SVARM 2014
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SWEDRES|SVARM 2014 The 2014 Swedish report from the monitoring of antibiotic resistance and antibiotic usage in human and veterinary medicine, Swedres-Svarm, is an integrated report from the Public Health Agency of Sweden and the National Veterinary Institute that includes data from humans, animals, and food of animal origin. The situation in Sweden regarding antibiotic resistance in bacteria from humans and animals is favourable when seen in an international perspective. This confirms that the Swedish strategies to promote rational use and to contain antibiotic resistance have been effective. The total consumption of antibiotics in humans has continued to decrease and positive trends regarding choices of antibiotics have also continued in 2014. Downward trends are also noted for consumption of antimicrobials in animals. Still, this year’s report also reports some unfavourable trends, for example, a large hospital in Sweden has been hit with VRE (vancomycin resistant enterococci) and there have been domestic human cases of Enterobacteriaceae with ESBLCARBA (extended spectrum beta-lactamase with activity against carbapenems) where the sources of infection are unknown. This highlights once again that efforts to optimize antibiotic use, prevent infections, and minimize dissemination of antibiotic resistance must be ongoing and continually improved activities. Focus areas: • ESBL-producing Escherichia coli with food as a potential dissemination route to humans • National campaign for improved patient safety • A national IT tool for surveillance of healthcare-associated infections and antibiotic use • MRSA in pigs in Sweden • Risk factors for antibiotic-resistant Escherichia coli in the faeces of preweaned dairy calves • SafeOrganic – antibiotic resistance in organic and conventional pig production in the EU • Svarmpat – monitoring resistance in pathogens from farm animals
The Public Health Agency of Sweden has a national responsibility for public health issues. The agency promotes good public health by building and disseminating knowledge to professionals involved in the area of public health, including infectious disease prevention. The National Veterinary Institute (SVA) is an expert authority within the field of risk assessment, diagnostics, and the prevention and control of infectious animal diseases. The Institute strives for good animal and human health through research, contingency planning, and communication of knowledge.
